NM_002880.4:c.709G>A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP4BS2
The NM_002880.4(RAF1):c.709G>A(p.Ala237Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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: 0.0000132 AC: 2AN: 152016Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251336Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135836
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727226
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152016Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74252
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1NN Pathogenic:1
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Noonan syndrome 5 Pathogenic:1
Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with supporting evidence (PMID: 31589614, 24777450, PS1_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000176, PM2). Missense changes are a common disease-causing mechanism (PP2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.682, PP3). Patient's phenotype is considered compatible with Rasopathy (3billlion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not specified Uncertain:1
Variant summary: RAF1 c.709G>A (p.Ala237Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.709G>A has been reported in the literature in individuals affected with Cardiomyopathy (Dhandapany_2014, Mazzaccara_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, and shows a mild increase in kinase activity (Dhandapany_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24777450, 36291626). ClinVar contains an entry for this variant (Variation ID: 142299). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:1
Identified in an adult patient with dilated cardiomyopathy but no other features consistent with a RASopathy disorder (Dhandapany et al., 2014); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies showed increased RAF1 kinase activity but uncertain effects downstream in the RAS/MAPK signaling (Dhandapany et al., 2014); This variant is associated with the following publications: (PMID: 31589614, 24777450) -
RASopathy Uncertain:1
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 237 of the RAF1 protein (p.Ala237Thr). This variant is present in population databases (rs587777588, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24777450). ClinVar contains an entry for this variant (Variation ID: 142299). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects RAF1 function (PMID: 24777450). 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