NM_002880.4:c.1688G>A
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1BS2
The NM_002880.4(RAF1):c.1688G>A(p.Arg563Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R563R) has been classified as Likely benign.
Frequency
Consequence
NM_002880.4 missense
Scores
Clinical Significance
Conservation
Publications
Genome browser will be placed here
ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000199 AC: 5AN: 251250 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461854Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16AN XY: 727234 show subpopulations
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74300 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
The RAF1 c.1688G>A; p.Arg563Gln variant (rs727504827), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 179378). This variant is found in the general population with an overall allele frequency of 0.002 % (5/251250 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.777). Due to limited information, the clinical significance of this variant is uncertain at this time. -
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Has not been previously published as pathogenic or benign to our knowledge -
not specified Uncertain:1
The Arg563Gln variant in SOS1 has now been identified by our laboratory in one a ffected individual and his reportedly unaffected mother. Computational predictio n tools and conservation analyses do not provide strong support for or against a n impact to the normal function of the protein. In summary, additional informati on is needed to assess the clinical significance of the Arg563Gln variant. -
Cardiovascular phenotype Uncertain:1
The p.R563Q variant (also known as c.1688G>A), located in coding exon 15 of the RAF1 gene, results from a G to A substitution at nucleotide position 1688. The arginine at codon 563 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a cardiomyopathy cohort (Akinrinade O et al. J Cardiovasc Transl Res, 2023 Dec;16:1287-1302). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
RASopathy Uncertain:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 563 of the RAF1 protein (p.Arg563Gln). This variant is present in population databases (rs727504827, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with RAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 179378). 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) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function with a positive predictive value of 95%. 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