3-12608842-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong
The NM_002880.4(RAF1):c.505G>C(p.Gly169Arg) variant causes a missense change. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G169G) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
RAF1
NM_002880.4 missense
NM_002880.4 missense
Scores
14
3
2
Clinical Significance
Conservation
PhyloP100: 6.10
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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_002880.4
PM2
Very rare variant in population databases, with high coverage;
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, 0.912
PP5
Variant 3-12608842-C-G is Pathogenic according to our data. Variant chr3-12608842-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 265535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RAF1 | NM_002880.4 | c.505G>C | p.Gly169Arg | missense_variant | 5/17 | ENST00000251849.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RAF1 | ENST00000251849.9 | c.505G>C | p.Gly169Arg | missense_variant | 5/17 | 1 | NM_002880.4 | 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:4Benign:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Nov 22, 2021 | RAF1 NM_002880.3 exon5 p.Gly169Arg (c.505G>C):This variant has not been reported in the literature and is not present in large control databases. However, this variant is present in ClinVar, reportedly identified de novo by another laboratory (Variation ID:265535). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2018 | The G169R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, the variant has been observed at GeneDx to occur apparently de novo in an affected individual. The G169R variant was not observed in large population cohorts (Lek et al., 2016). The G169R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
LEOPARD syndrome 2;C1969057:Noonan syndrome 5 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Aug 01, 2017 | RAF1 NM_002880.3 exon5 p.Gly169Arg (c.505G>C):This variant has not been reported in the literature and is not present in large control databases. However, this variant is present in ClinVar, reportedly identified de novo by another laboratory (Variation ID:265535). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic. - |
RASopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 06, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 169 of the RAF1 protein (p.Gly169Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RAF1-related conditions (external communication). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 265535). 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. For these reasons, this variant has been classified as Pathogenic. - |
Noonan syndrome Benign:1
| Likely benign, flagged submission | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;.
Vest4
MutPred
Gain of catalytic residue at G169 (P = 0.0549);Gain of catalytic residue at G169 (P = 0.0549);.;
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