Variant interpretation using population databases: Lessons from gnomAD

Gudmundsson, Sanna; Singer-Berk, Moriel; Watts, Nicholas A.; Phu, William; Goodrich, Julia K.; Solomonson, Matthew; Rehm, Heidi L.; MacArthur, Daniel G.; O’Donnell-Luria, Anne

doi:10.1002/humu.24309

Cited by 323 publications

(260 citation statements)

References 58 publications

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“…Yet solely one study has explored the prevalence of LEP variants in the general population using these reference datasets (17). As of today, the gnomAD database is the largest publicly available databases containing data of genetic variants (25). More than 125,000 exome and 15,000 whole genome sequence datasets are contained in gnomAD v2.1.1 (18).…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…Predictions by SIFT, FATHMM-MKL and PROVEAN were obtained with the help of the Variant Effect Predictor (VEP, 24). For LoF, gnomAD presents predictions whether the respective LoF variant is a high-or low-confidence LoF based on results of either the LOFTEE tool or a manual curation, shown below the information of VEP on gnomAD's variant page (18,25). SIFT classifies variants as either 'tolerated' or 'deleterious', while PolyPhen2 categorizes the mutations into 'benign', 'possibly damaging' and 'probably damaging'.…”

Section: Leptin Variants and Their Predicted Functional Implicationsmentioning

confidence: 99%

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Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database

Rajcsanyi

Zheng

Fischer‐Posovszky

et al. 2022

Preprint

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Homozygosity for pathogenic variants in the leptin gene leads to congenital leptin deficiency causing early-onset extreme obesity. This monogenic form of obesity has mainly been detected in patients from consanguineous families. Prevalence estimates for the general population using the Exome Aggregation Consortium (ExAC) database reported a low frequency of leptin mutations. One in approximately 15 million individuals will be homozygous for a deleterious leptin variant. With the present study, we aimed to extend these findings utilizing the augmented Genome Aggregation Database (gnomAD) v2.1.1 including more than 140,000 samples. In total, 68 non-synonymous and 7 loss-of-function (LoF) leptin variants were deposited in gnomAD. By predicting functional implications with the help of in silico tools, like SIFT, PolyPhen2 and MutationTaster2021, the prevalence of hetero- and homozygosity for putatively pathological variants (n = 32; pathogenic prediction by at least two tools) in the leptin gene were calculated. Across all populations, the estimated prevalence for heterozygosity for functionally relevant variants was approximately 1:2,100 and 1:17,860,000 for homozygosity. This prevalence deviated between the individual populations. Accordingly, people from South Asia were at greater risk to carry a possibly damaging leptin variant than individuals of other ancestries. Generally, this study emphasises the scarcity of deleterious leptin variants in the general population with varying prevalence for distinct study groups.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Leptin Variants and Their Predicted Functional Implicationsmentioning

confidence: 99%

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Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database

Rajcsanyi

Zheng

Fischer‐Posovszky

et al. 2022

Preprint

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“…In what follows, we have used the gnomAD database 12 (as of November 18, 2021) to assess the frequency of MPS-related "germline" variants in JAK2, CALR, and MPL in "normal" populations. Specifically, we have based our analysis on the gnomAD v2.…”

Section: Methodsmentioning

confidence: 99%

“…10,11 Here, we use data from the gnomAD database (https://gnomad.broadinstitute.org), which aggregates both exome and genome sequencing data from a variety of large-scale projects to explore the frequency of MPS-related "germline" variants in "normal" populations. 12 We provide a series of genetic arguments that cast doubts on the inherited nature of (at least a proportion of ) such variants.…”

Section: Introductionmentioning

confidence: 99%

Pathogenic “germline” variants associated with myeloproliferative disorders in apparently normal individuals: Inherited or acquired genetic alterations?

Veitia

Innan

2022

Clinical Genetics

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Myeloproliferative syndromes (MPS) are hematologic malignancies due to the expansion of an abnormal hematopoietic stem cell. They include chronic myeloid leukemia (CML) and non-CML MPS such as polycythemia vera, essential thrombocythemia and primary myelofibrosis. The latter are distinguished by somatic pathogenic variants affecting JAK2, CALR, or MPL genes. Apparent germline pathogenic variants have been reported in the general population. Here, we found that two gnomAD data-sets report more homozygotes than expected for the JAK2 c.1849G > T(Val617Phe) variant. We propose that somatic gene conversion can explain the presence of those unexpected homozygotes in normal populations. Consistently, homozygous individuals are older than 65 years. We also found a lower-than-expected frequency of the JAK2 variant in younger individuals suggesting that somatic mutation can underlie its presence in (at least some) heterozygotes. Regarding pathogenic variants in MPL and CALR, they are also present in the gnomAD data-sets explored. However, we cannot conclude that such seemingly germline variants are in fact somatic alterations. These results suggest that apparently normal individuals bearing MPS-related variants can be subclinical/ undiagnosed MPS cases of somatic origin. It would be interesting to assess the hematologic phenotype of such individuals and the presence of the relevant variants in other tissues.

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POLR3A‐related disorders: From spastic ataxia to generalised dystonia and long‐term efficacy of deep brain stimulation

Yau,

Ashton,

Mulroy

et al. 2024

Ann Clin Transl Neurol

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While biallelic POLR3A loss‐of‐function variants are traditionally linked to hypomyelinating leukodystrophy, patients with a specific splice variant c.1909+22G>A manifest as adolescent‐onset spastic ataxia without overt leukodystrophy. In this study, we reported eight new cases, POLR3A‐related disorder with c.1909+22 variant. One of these patients showed expanded phenotypic spectrum of generalised dystonia and her sister remained asymptomatic except for hypodontia. Two patients with dystonic arm tremor responded to deep brain stimulation. In our systemic literature review, we found that POLR3A‐related disorder with c.1909+22 variant has attenuated disease severity but frequency of dystonia and upper limb tremor did not differ among genotypes.

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Variant interpretation using population databases: Lessons from gnomAD

Cited by 323 publications

References 58 publications

Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database

Prevalence Estimates of Putatively Pathogenic Leptin Variants in the gnomAD Database

Pathogenic “germline” variants associated with myeloproliferative disorders in apparently normal individuals: Inherited or acquired genetic alterations?

POLR3A‐related disorders: From spastic ataxia to generalised dystonia and long‐term efficacy of deep brain stimulation

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