chr3-12618656-A-C

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP5BS4

This summary comes from the ClinGen Evidence Repository: The c.66T>G (p.Phe22Leu) variant has been identified in patients with clinical features of a RASopathy, however the variant did not segregate with disease in affected family members (BS4; GeneDx, Partners LMM, Invitae internal data GTR ID's: 26957, 21766, 500031; ClinVar SCV000218672.4; SCV000061358.5). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; LMM internal data; SCV000061358.5). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA134746/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

RAF1
NM_001354694.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:4

Conservation

PhyloP100: 1.01

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP5

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

BS4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAF1	NM_002880.4 link	c.66T>G	p.Phe22Leu	missense_variant	Exon 2 of 17	ENST00000251849.9	NP_002871.1	P04049-1L7RRS6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9 link	c.66T>G	p.Phe22Leu	missense_variant	Exon 2 of 17	1	NM_002880.4	ENSP00000251849.4		P04049-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251480

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000131

AC:

191

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000169

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000812

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RASopathy

Uncertain:1Benign:1

Apr 03, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.66T>G (p.Phe22Leu) variant has been identified in patients with clinical features of a RASopathy, however the variant did not segregate with disease in affected family members (BS4; GeneDx, Partners LMM, Invitae internal data GTR ID's: 26957, 21766, 500031; ClinVar SCV000218672.4; SCV000061358.5). This variant has been identified in a patient with an alternate molecular basis for disease (BP5; LMM internal data; SCV000061358.5). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS4, BP5. -

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 22 of the RAF1 protein (p.Phe22Leu). This variant is present in population databases (rs397516824, gnomAD 0.01%). This missense change has been observed in individual(s) with Noonan syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 40583). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAF1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Feb 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Cardiovascular phenotype

Benign:1

Aug 29, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RAF1-related disorder

Benign:1

Aug 20, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.37

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.8

L;L

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.020

D;D

Sift4G

Benign

0.23

T;T

Polyphen

0.060

B;.

Vest4

0.60

MutPred

0.37

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MVP

0.75

MPC

1.4

ClinPred

0.14

GERP RS

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.37

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

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