rs886039607

Variant names:

• chr3-12608842-C-G
• rs886039607
• NM_002880.4:c.505G>C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RAF1 NM_002880.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 B:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RAF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 39 curated benign missense variants. Gene score misZ: 2.4628 (below the threshold of 3.09). Trascript score misZ: 3.4185 (above the threshold of 3.09). GenCC associations: The gene is linked to 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 rank	MANE	Protein	UniProt
RAF1	NM_002880.4	c.505G>C	p.Gly169Arg	missense_variant	Exon 5 of 17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9	c.505G>C	p.Gly169Arg	missense_variant	Exon 5 of 17	1	NM_002880.4	ENSP00000251849.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Benign:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LEOPARD syndrome 2;C1969057:Noonan syndrome 5;C4014656:Dilated cardiomyopathy 1NN Pathogenic:1

Nov 22, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 20, 2018

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 01, 2017

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

-

Service de Génétique Moléculaire, Hôpital Robert Debré

Significance: Likely benign

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	1.9	L;L;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.81
MutPred		0.54		Gain of catalytic residue at G169 (P = 0.0549);Gain of catalytic residue at G169 (P = 0.0549);.;
MVP		0.96
MPC		1.5
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886039607; hg19: chr3-12650341;