3-12604188-G-C
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Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_002880.4(RAF1):c.782C>G(p.Pro261Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. P261A) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
RAF1
NM_002880.4 missense
NM_002880.4 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 10.0
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 17 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 chr3-12604189-G-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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.865
PP5
Variant 3-12604188-G-C is Pathogenic according to our data. Variant chr3-12604188-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 40606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-12604188-G-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RAF1 | NM_002880.4 | c.782C>G | p.Pro261Arg | 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.782C>G | p.Pro261Arg | missense_variant | 7/17 | 1 | NM_002880.4 | ENSP00000251849 | P3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 14, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 21, 2022 | Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with Noonan syndrome in the published literature (van Trier et al., 2015); This variant is associated with the following publications: (PMID: 30692697, 24803665, 28777121, 25862627, 26266034, 30384889, 32668031, 32981126, 24957944, 9689060, 15520807, 29493581, 19020799) - |
Noonan syndrome 5 Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Nov 18, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 25, 2022 | The c.782C>G;p.(Pro261Arg) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 40606; PMID: 28777121; 26266034; 25862627; 22824796; 22465605) -PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (PMID: 22824796; 22465605) - PM1. This variant is not present in population databases (rs397516828- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 120246) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 26266034) - PM6. Missense variant in RAF1 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic - |
RASopathy Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 09, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro261 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603482, 17603483, 20683980, 21784453, 22465605). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 40606). This missense change has been observed in individual(s) with Noonan syndrome (NS) (PMID: 25862627, 26266034, 28777121). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 261 of the RAF1 protein (p.Pro261Arg). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 10, 2017 | Variant summary: The RAF1 c.782C>G (p.Pro261Arg) variant involves the alteration of a highly conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121388 control chromosomes and has been reported in the literature in at least 2 Noonan Syndrome patients, one in whom the variant was absent in both parents (assumed de novo [Ratola_2015, VanTrier_2015]). Other variants affecting the same codon (Pro261Ala, Pro261Leu) have been classified as pathogenic/likely pathogenic by our lab, indicating the variant to be located in a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. - |
Noonan syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 17, 2016 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Apr 10, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of MoRF binding (P = 5e-04);Gain of MoRF binding (P = 5e-04);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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