rs7609455

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005633.4(SOS1):c.195A>C(p.Arg65=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,613,400 control chromosomes in the GnomAD database, including 628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.036 ( 303 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 325 hom. )

Consequence

SOS1
NM_005633.4 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:15

Conservation

PhyloP100: 0.782

Variant links:

Genes affected

SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

SOS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 2-39067646-T-G is Benign according to our data. Variant chr2-39067646-T-G is described in ClinVar as [Benign]. Clinvar id is 40643.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-39067646-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.782 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4 linkuse as main transcript	c.195A>C	p.Arg65=	synonymous_variant	2/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8 linkuse as main transcript	c.195A>C	p.Arg65=	synonymous_variant	2/23	1	NM_005633.4	A1	Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.0358

AC:

5448

AN:

152118

Hom.:

299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0246

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0229

Gnomad SAS

AF:

0.00662

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.0273

GnomAD3 exomes

AF:

0.0122

AC:

3058

AN:

251384

Hom.:

138

AF XY:

0.00976

AC XY:

1326

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.118

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0178

Gnomad SAS exome

AF:

0.00794

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.000783

Gnomad OTH exome

AF:

0.00783

GnomAD4 exome

AF:

0.00534

AC:

7801

AN:

1461164

Hom.:

325

Cov.:

AF XY:

0.00501

AC XY:

3640

AN XY:

726882

show subpopulations

Gnomad4 AFR exome

AF:

0.120

Gnomad4 AMR exome

AF:

0.0129

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.0334

Gnomad4 SAS exome

AF:

0.00742

Gnomad4 FIN exome

AF:

0.00120

Gnomad4 NFE exome

AF:

0.000416

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.0359

AC:

5465

AN:

152236

Hom.:

303

Cov.:

AF XY:

0.0357

AC XY:

2655

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.116

Gnomad4 AMR

AF:

0.0246

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0229

Gnomad4 SAS

AF:

0.00621

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.00955

Hom.:

Bravo

AF:

0.0409

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 18, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 05, 2007	- -
Benign, no assertion criteria provided	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

RASopathy

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Baylor Genetics	-	Variant classified using ACMG guidelines -
Benign, reviewed by expert panel	curation	ClinGen RASopathy Variant Curation Expert Panel	Apr 18, 2017	The filtering allele frequency of the c.195A>C (p.Arg65=) variant in the SOS1 gene is 10.978% (1192/10346) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Noonan syndrome 4

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 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. -

Fibromatosis, gingival, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Noonan syndrome and Noonan-related syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

Cadd

Benign

9.3

Dann

Benign

0.75

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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