rs200278862
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_022114.4(PRDM16):c.1537G>A(p.Gly513Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000154 in 1,611,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_022114.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000921 AC: 14AN: 151956Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000933 AC: 23AN: 246486Hom.: 0 AF XY: 0.000127 AC XY: 17AN XY: 133764
GnomAD4 exome AF: 0.000160 AC: 234AN: 1459330Hom.: 0 Cov.: 32 AF XY: 0.000158 AC XY: 115AN XY: 725808
GnomAD4 genome AF: 0.0000921 AC: 14AN: 151956Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74218
ClinVar
Submissions by phenotype
not provided Uncertain:6
BP4 -
Found in a 23-year-old female with unexplained postpartum sudden cardiac arrest, along with 5 other VUSs. p.Gly513Ser (c.1537G>A) in exon 9 of the PRDM16 gene (NM_022114.3; ENST00000270722.9) Chromosome location 1:3328298 G / A Based on the information reviewed below, including the lack of case data, prevalence in population databases, and this variant's being the default in multiple other species, we classify it as Variant of Uncertain Significance (VUS), Probably Benign. The PRDM16 gene currently has no well-established disease association; however, there is preliminary evidence supporting a correlation with autosomal dominant left ventricular noncompaction (LVNC) (MedGen UID: 349005) and dilated cardiomyopathy (DCM) (OMIM: 615373). This variant has not been reported in the literature in association with disease, according to the Invitae report. This is a nonconservative amino acid change, resulting in the replacement of a nonpolar Glycine with a polar Serine. Glycine at this location is fairly well conserved across ~100 vertebrate species for which we have data, but it is instead a Serine in at least 3 mammalian species. There are no Likely Pathogenic or Pathogenic missense variants listed in ClinVar within 10 amino acids to either side. According to the Invitae report, algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant was reported in 24 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Overall MAF: 0.009%. Specifically, the variant was observed in 20 non-Finnish Europeans (for the highest allele frequency: 0.016%), 2 Latinos, and 2 African ancestry individuals. Invitae notes that it has an allele count higher than expected for a pathogenic variant. There is good coverage at this site. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases. -
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Has not been previously published as pathogenic or benign in association with PRDM16-related disorder to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27956748) -
not specified Uncertain:1
Variant summary: PRDM16 c.1537G>A (p.Gly513Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.3e-05 in 246486 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in PRDM16 causing Dilated Cardiomyopathy (3.6e-05), suggesting that the variant may be a polymorphism found primarily in populations of Non-Finnish European origin. c.1537G>A has been reported in the literature as a VUS in a setting of multipanel gene testing in an individual affected with Dilated Cardiomyopathy (Rieger_2019). This report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Left ventricular noncompaction 8 Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 513 of the PRDM16 protein (p.Gly513Ser). This variant is present in population databases (rs200278862, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PRDM16-related conditions. ClinVar contains an entry for this variant (Variation ID: 241421). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at