chr3-12612058-T-C

Position:

chr3-12612058-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.212A>G (p.Asn71Ser) variant in the RAF1 gene is 0.14% for Latino chromosomes by the Exome Aggregation Consortium (24/11578 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA134721/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

RAF1
NM_002880.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: 4.54

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 Benign. Variant got -8 ACMG points.

BA1

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.212A>G	p.Asn71Ser	missense_variant	3/17	ENST00000251849.9	NP_002871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAF1	ENST00000251849.9 linkuse as main transcript	c.212A>G	p.Asn71Ser	missense_variant	3/17	1	NM_002880.4	ENSP00000251849	P3	P04049-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000247

AC:

AN:

251492

Hom.:

AF XY:

0.000235

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000841

AC:

123

AN:

1461680

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000190

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 16, 2013	Variant classified as Uncertain Significance - Favor Benign. The Asn71Ser varian t in RAF1 has not been previously reported in the literature nor previously been identified by our laboratory. This variant has been identified in 0.01% (1/8600 ) of European American chromosomes from a broad population by the NHLBI Exome Se quencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs184022679). Computa tional analyses (biochemical amino acid properties, conservation, AlignGVGD, Pol yPhen2, and SIFT) suggest that the Asn71Ser variant may not impact the normal fu nction of the protein, though this information is not predictive enough to rule out pathogenicity. Of note, the Shrew (a species in the Mammalian class) also ca rries a serine (Ser) at amino acid position 71 in the RAF1 gene. In summary, add itional information is needed to fully assess the clinical significance of this variant. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 27, 2021	Variant summary: RAF1 c.212A>G (p.Asn71Ser) results in a conservative amino acid change located in the Raf-like Ras-binding (IPR003116) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251492 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 56 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.212A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four other ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	RAF1: BS1 -

RASopathy

Benign:2

Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 03, 2017	The filtering allele frequency of the c.212A>G (p.Asn71Ser) variant in the RAF1 gene is 0.14% for Latino chromosomes by the Exome Aggregation Consortium (24/11578 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2017

This alteration is classified as 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

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2021

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

Benign

0.14

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.54

D;.

Eigen

Benign

-0.073

Eigen_PC

Benign

0.054

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.1

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.85

N;N

REVEL

Benign

0.19

Sift

Benign

0.47

T;T

Sift4G

Benign

0.46

T;T

Polyphen

0.11

B;.

Vest4

0.40

MVP

0.70

MPC

0.40

ClinPred

0.024

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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