chr3-12584539-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP5BS2
The NM_002880.4(RAF1):c.1922C>T(p.Thr641Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000805 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_002880.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251256Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135802
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727246
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1NN Pathogenic:3
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 24777450). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71; 3Cnet: 0.89). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000142298). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
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The missense variant p.T641M in RAF1 (NM_002880.4) has been reported previously in patients affected with childhood onset cardiomyopathy (Dhandapany S et al). Functional studies in zebrafish revealed a heart failure phenotype. It has been submitted to the ClinVar database as Pathogenic. There is a moderate physicochemical difference between threonine and methionine. The p.T641M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 641 of RAF1 is conserved in all mammalian species. The nucleotide c.1922 in RAF1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
not provided Uncertain:2
Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar, but additional evidence is not available (ClinVar Variant ID# 142298; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 31589614, 24777450) -
RAF1: PS3:Moderate, PS4:Moderate, PM2:Supporting -
Primary dilated cardiomyopathy Pathogenic:1
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RASopathy Pathogenic:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 641 of the RAF1 protein (p.Thr641Met). This variant is present in population databases (rs587777587, gnomAD 0.006%). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 24777450). ClinVar contains an entry for this variant (Variation ID: 142298). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RAF1 protein function. Experimental studies have shown that this missense change affects RAF1 function (PMID: 24777450). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Cardiovascular phenotype Uncertain:1
The p.T641M variant (also known as c.1922C>T), located in coding exon 16 of the RAF1 gene, results from a C to T substitution at nucleotide position 1922. The threonine at codon 641 is replaced by methionine, an amino acid with similar properties. This variant has been reported in a dilated cardiomyopathy cohort and prenatal anomaly cohort (Dhandapany PS et al. Nat Genet, 2014 Jun;46:635-639; Zhu X et al. Ultrasound Obstet Gynecol, 2022 Dec;60:780-792). Functional studies suggest the variant had kinase activities that were mildly increased; however, additional evidence is needed to confirm this finding (Dhandapany PS et al. Nat Genet, 2014 Jun;46:635-639). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at