rs368796800
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM1PP2BP6_StrongBS2
The NM_002880.4(RAF1):c.835G>A(p.Asp279Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★).
Frequency
Consequence
NM_002880.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.835G>A | p.Asp279Asn | missense_variant, splice_region_variant | 8/17 | ENST00000251849.9 | NP_002871.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.835G>A | p.Asp279Asn | missense_variant, splice_region_variant | 8/17 | 1 | NM_002880.4 | ENSP00000251849.4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152116Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251426Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135904
GnomAD4 exome AF: 0.0000171 AC: 25AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727224
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152234Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74436
ClinVar
Submissions by phenotype
RASopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 04, 2024 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 279 of the RAF1 protein (p.Asp279Asn). This variant is present in population databases (rs368796800, gnomAD 0.03%). 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: 181510). 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. - |
Uncertain significance, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Sep 24, 2019 | The c.835G>A (p.Asp279Asn) variant in RAF1 has been identified in 0.01786% (lower bound of the 95% CI of 7/18394) of East Asian chromosomes in gnomAD (BS1 not met; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been observed in several individuals with varying clinical presentations that lack clear associations with a RASopathy. It was also seen in 13 individuals clinically unaffected with a RASopathy (BS2; GeneDx internal data). In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: BS2. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 22, 2021 | The p.D279N variant (also known as c.835G>A), located in coding exon 7 of the RAF1 gene, results from a G to A substitution at nucleotide position 835. This variant impacts the first base pair of coding exon 7. The aspartic acid at codon 279 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 01, 2024 | Variant summary: RAF1 c.835G>A (p.Asp279Asn) alters a conserved nucleotide located at the exon-intron boundary of the RAF1 gene resulting in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. 5/5 computational tools via ALAMUT predict no significant impact on normal splicing. Another in-silico tool for assessing the pathogenicity of synonymous variants, namely TraP (Transcript-inferred Pathogenicity, Gelfman_2017) predicts this variant to be benign. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 6e-05 in 251426 control chromosomes (gnomAD). The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.835G>A in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 181510). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 09, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at