3-12604202-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP2PP5_Very_Strong
The NM_002880.4(RAF1):c.768G>C(p.Arg256Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R256G) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
RAF1
NM_002880.4 missense
NM_002880.4 missense
Scores
6
11
2
Clinical Significance
Conservation
PhyloP100: -0.0880
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 Pathogenic. Variant got 15 ACMG points.
PM1
In a compositionally_biased_region Polar residues (size 47) in uniprot entity RAF1_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_002880.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-12604204-T-C is described in Lovd as [Pathogenic].
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RAF1. . Gene score misZ 2.4628 (greater than the threshold 3.09). Trascript score misZ 3.4185 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome 5, dilated cardiomyopathy 1NN, Noonan syndrome with multiple lentigines, Noonan syndrome, cardiofaciocutaneous syndrome, familial isolated dilated cardiomyopathy, LEOPARD syndrome 2, Costello syndrome.
PP5
Variant 3-12604202-C-G is Pathogenic according to our data. Variant chr3-12604202-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAF1 | NM_002880.4 | c.768G>C | p.Arg256Ser | missense_variant | 7/17 | ENST00000251849.9 | NP_002871.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAF1 | ENST00000251849.9 | c.768G>C | p.Arg256Ser | missense_variant | 7/17 | 1 | NM_002880.4 | ENSP00000251849.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Noonan syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 30, 2011 | A different nucleotide change, 768G>T, leading to an identical amino acid change , Arg256Ser, has been reported previously in the literature in one individual wi th Noonan syndrome (Pandit, 2007). The 768G>T variant was not identified in 210 European controls. R256 lies in a domain critical for normal RAF1 protein functi on, and many pathogenic variants have been identified in this region. This resid ue is completely conserved across evolutionarily distinct species and computatio nal analyses (PolyPhen2, SIFT, AlignGVGD) predict that this variant will impact the normal function of the protein. It should be noted that the sensitivity and specificity of these computational programs has not been determined by our labor atory. It is likely that this variant is pathogenic and responsible for the cli nical features observed in this individual. - |
RASopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 11, 2023 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 256 of the RAF1 protein (p.Arg256Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Noonan syndrome (PMID: 17603483; Invitae). ClinVar contains an entry for this variant (Variation ID: 44632). 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. Experimental studies have shown that this missense change affects RAF1 function (PMID: 20679480). This variant disrupts the p.Arg256 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of glycosylation at S252 (P = 0.0093);Gain of glycosylation at S252 (P = 0.0093);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at