rs150054973

Positions:

chr3-12600397-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS2

The NM_002880.4(RAF1):c.853A>G(p.Ser285Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

RAF1
NM_002880.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.40

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1

In a region_of_interest Disordered (size 114) in uniprot entity RAF1_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_002880.4

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.048469543).

BP6

Variant 3-12600397-T-C is Benign according to our data. Variant chr3-12600397-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263589.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAF1	NM_002880.4 linkuse as main transcript	c.853A>G	p.Ser285Gly	missense_variant	8/17	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.853A>G	p.Ser285Gly	missense_variant	8/17	1	NM_002880.4	ENSP00000251849.4		P04049-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251420

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000173

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2019

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 263589; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Noonan syndrome

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2019

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. -

RASopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.40

T;.;T

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.048

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

L;.;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.52

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.35

T;T;T

Sift4G

Benign

0.48

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.30

MVP

0.73

MPC

0.42

ClinPred

0.031

GERP RS

0.19

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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