rs730880382

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1193G>T variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by leucine at amino acid 398 (p.Arg398Leu). This variant is absent from gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.861, which is above the threshold of 0.7 and is evidence that correlates with impact to RAF1 function. The variant is also entirely conserved in the UCSC database, and Alamut does not predict an impact to splicing (PP3). This variant has been identified in at least 5 probands with variable phenotypic features, with two of them having a clinical suspicion of Noonan syndrome (PS4 not met; Rady Children's Institute for Genomic Medicine internal communications, Invitae; SCV000209025.5; SCV000207671.1; SCV000552095.2, SCV000552095.6). In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM2_supporting, PP3. (Specification Version 2.1, 9/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA235336/MONDO:0021060/040

Frequency

Genomes: not found (cov: 32)

Consequence

RAF1
NM_002880.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:4

Conservation

PhyloP100: 7.90

Variant links:

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]

RAF1 links:

RAF1 (HGNC:):

RAF1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4 linkuse as main transcript	c.1193G>T	p.Arg398Leu	missense_variant, splice_region_variant	11/17	ENST00000251849.9	NP_002871.1	P04049-1L7RRS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9 linkuse as main transcript	c.1193G>T	p.Arg398Leu	missense_variant, splice_region_variant	11/17	1	NM_002880.4	ENSP00000251849.4		P04049-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RASopathy

Pathogenic:1Uncertain:1

Uncertain significance, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Sep 17, 2024	The c.1193G>T variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by leucine at amino acid 398 (p.Arg398Leu). This variant is absent from gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.861, which is above the threshold of 0.7 and is evidence that correlates with impact to RAF1 function. The variant is also entirely conserved in the UCSC database, and Alamut does not predict an impact to splicing (PP3). This variant has been identified in at least 5 probands with variable phenotypic features, with two of them having a clinical suspicion of Noonan syndrome (PS4 not met; Rady Children's Institute for Genomic Medicine internal communications, Invitae; SCV000209025.5; SCV000207671.1; SCV000552095.2, SCV000552095.6). In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM2_supporting, PP3. (Specification Version 2.1, 9/17/2024) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 28, 2023	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 398 of the RAF1 protein (p.Arg398Leu). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of RAF1-related RASopathy and/or clinical features of RASopathy spectrum disorders (Invitae). ClinVar contains an entry for this variant (Variation ID: 40614). 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 disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2017	The c.1193 G>T variant in the RAF1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1193 G>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models predict that c.1193 G>T damages the splice donor site in intron 11, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of the c.1193 G>T change in this individual is unknown. If c.1193 G>T does not alter splicing, it will result in the R398L missense change. The R398L 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. While this substitution occurs at a position that is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. In vitro functional studies indicate that another missense substitution (R398A) at this residue leads to reduction of RAF1 kinase activity (Baljuls et al., 2011); however, increased activity is expected for RASopathy disorders. We interpret c.1193 G>T as a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -

Noonan syndrome 5

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Nov 07, 2019

This variant has been reported in the literature (PMID: 30095857, 29493581) and is present in ClinVar (Variation ID: 49084). The residue p.Arg398 has been characterized in-vitro as functionally important (PMID: 21454547, 10801816, 12925535). The c.1193G>T, p.Arg398Leu is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. This alteration affect the last nucleotide of exon 11 of RAF1 and in-silico splicing algorithms (SpliceSiteFinder-like, MaxEntScan, NNSplice, GeneSplicer) predict that the variant weakens the canonical splice site. In addition, in-silico analyses for the mssense change support a deleterious effect of this variant on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1193G>T, p.Arg398Leu variant is classified as Likely Pathogenic. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 15, 2021

RAF1 NM_002880.3 exon 11 p.Arg398Leu (c.1193G>T): This variant has not been reported in the literature in association with disease and is not present in large control databases. This variant is present in ClinVar with classifications ranging from Uncertain significance to likely pathogenic, including as a Uncertain significance by the ClinGen RASopathy Variant Curation Expert Panel (Variation ID:40614). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. RAF1 has a low rate of benign missense variation, and pathogenic missense variants are enriched in affected individuals; however, this variant occurs in a region in which pathogenic variants are uncommon (Gelb 2018 PMID: 29493581). Of note, this variant occurs in the splice region and computational splice prediction tools support a possible impact to splicing; however, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;.;D

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.85

L;.;.

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.92

MutPred

0.73

Loss of MoRF binding (P = 0.0144);.;.;

MVP

0.98

MPC

2.6

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over