rs876657965
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2PP2BP6_Very_Strong
The NM_002880.4(RAF1):c.124_125delinsAT(p.Ala42Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A42T) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
RAF1
NM_002880.4 missense
NM_002880.4 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.41
Genes affected
RAF1 (HGNC:9829): (Raf-1 proto-oncogene, serine/threonine kinase) This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, RAF1
BP6
?
Variant 3-12618597-GC-AT is Benign according to our data. Variant chr3-12618597-GC-AT is described in ClinVar as [Likely_benign]. Clinvar id is 229175.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.124_125delinsAT | p.Ala42Ile | missense_variant | 2/17 | ENST00000251849.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.124_125delinsAT | p.Ala42Ile | missense_variant | 2/17 | 1 | NM_002880.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Likely benign
Submissions summary: Uncertain:5Benign:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 05, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 26, 2017 | - - |
not specified Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2015 | The p.Ala42Ile variant in RAF1 has not been previously reported in individuals w ith a RASopathy, but has been identified by our laboratory in 1 Caucasian adult with LNVC. This variant represents two adjacent base pair changes that are prese nt on the same copy of the RAF1 gene and result in the substitution of a single alanine (Ala) residue at position 42 with an isoleucine (Ile). These are reporte d as 2 separate changes in the ExAC database (c.124G>A and c.125C>T), each prese nt in 25/66738 European chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs115499992 and rs200856000) but have been confirmed to be present in cis (pers onal communication). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ala42Ile variant is uncertain. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 05, 2019 | Variant summary: RAF1 c.124_125delinsAT (p.Ala42Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 277244 control chromosomes. The observed variant frequency is approximately 12-fold over 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. c.124_125delinsAT has been reported in the literature in an individual affected with hypertrophic cardiomyopathy (Bottillo_2016). This report does not provide an unequivocal conclusion about association of the variant with Noonan Syndrome and Related Conditions. A co-occurrence with another pathogenic variant has been internally reported (PTPN11 c.923A>G, p.Asn308Ser), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
RASopathy Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 31, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 42 of the RAF1 protein (p.Ala42Ile). This variant is present in population databases (no rsID available, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with RAF1-related conditions (PMID: 26656175, 33500567). ClinVar contains an entry for this variant (Variation ID: 229175). 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. - |
Likely benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Sep 24, 2019 | The c.124_125delinsAT (p.Ala42Ile) variant in RAF1 is reported in population databases as two contiguous missense variants: c.124G>A and c.125C>T in cis in 27/64,595 (0.03%) European individuals in gnomAD. This meets the cut off set by the ClinGen RASopathy Variant Curation Expert Panel to apply BS1. This variant has been observed in at least 22 individuals (SCV000858114.1, SCV000698121.1, SCV000272341.3, SCV000552093.5, GeneDx internal data). This variant was observed in an individual with an alternate molecular basis for disease (BP5; SCV000698121.1 ). Computational prediction tools and conservation analysis suggest that the p.Ala42Ile variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5, BP4. - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 30, 2018 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at