rs8192671

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.3032A>G (p.Asn1011Ser) variant in the SOS1 gene is 0.26% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (197/66620 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/CA136129/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 4 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:17

Conservation

PhyloP100: 5.80

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

Noonan syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Noonan syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
fibromatosis, gingival, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hereditary gingival fibromatosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cardiofaciocutaneous syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Costello syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

SOS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4 link	c.3032A>G	p.Asn1011Ser	missense_variant	Exon 19 of 23	ENST00000402219.8	NP_005624.2	Q07889-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 link	c.3032A>G	p.Asn1011Ser	missense_variant	Exon 19 of 23	1	NM_005633.4	ENSP00000384675.2		Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.00158

AC:

240

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00281

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00176

AC:

442

AN:

251138

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000878

Gnomad NFE exome

AF:

0.00315

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00246

AC:

3575

AN:

1455044

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

1761

AN XY:

724382

show subpopulations

African (AFR)

AF:

0.000360

AC:

AN:

33332

American (AMR)

AF:

0.000671

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26066

East Asian (EAS)

AF:

0.00

AC:

AN:

39502

South Asian (SAS)

AF:

0.000430

AC:

AN:

86098

European-Finnish (FIN)

AF:

0.00172

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00299

AC:

3302

AN:

1106096

Other (OTH)

AF:

0.00166

AC:

100

AN:

60108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

149

299

448

598

747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00158

AC:

240

AN:

152318

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

108

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000481

AC:

AN:

41584

American (AMR)

AF:

0.000981

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00281

AC:

191

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00238

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00189

AC:

230

Asia WGS

AF:

0.000289

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 20, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 14, 2008

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:5

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SOS1: BS1 -

RASopathy

Benign:2

Apr 03, 2017

ClinGen RASopathy Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The filtering allele frequency of the c.3032A>G (p.Asn1011Ser) variant in the SOS1 gene is 0.26% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (197/66620 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). -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Noonan syndrome 4

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1

Benign:1

Jul 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 31, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Noonan syndrome and Noonan-related syndrome

Benign:1

Mar 23, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;D;T

Eigen

Benign

-0.065

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

.;D;D

M_CAP

Benign

0.0053

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

N;N;.

PhyloP100

5.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.079

Sift

Benign

0.10

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.0050

B;B;.

Vest4

0.37

MVP

0.40

MPC

0.079

ClinPred

0.020

GERP RS

5.4

Varity_R

0.29

gMVP

0.43

Mutation Taster

=98/2

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over