chr2-38986226-G-C

Position:

chr2-38986226-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS1BP5BP4

This summary comes from the ClinGen Evidence Repository: The c.3600C>G (p.Asp1200Glu) variant in the SOS1 gene has been identified in at least 6 individuals without detailed phenotypic information as well as one patient with an alternative molecular basis for disease in the BRAF gene (BP5; EGL, Invitae, GeneDx internal data, GTR Lab ID: 500060, 500031, 26957; SCV000854873.1, SCV000553268.3, SCV000209087.11). The filtering allele frequency of the c.3600C>G (p.Asp1200Glu) variant is 0.025% for European (non-Finnish) exomes by the gnomAD database (40/251300 with 95% CI) which is strong evidence to suggest that the variant may be benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BS1). Of note, the c.3600C>A change that also results in p.Asp1200Glu has been identified in one patient with a RASopathy but this variant has not met criteria to be classified as pathogenic and therefore PM5 is not met (Partners LMM internal data; GTR Lab ID: 21766; SCV000062231.5). Computational prediction tools and conservation analysis suggest that the p.Asp1200Glu variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP4, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA297240/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:9

Conservation

PhyloP100: -0.0430

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 Likely_benign. Variant got -6 ACMG points.

BP4

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

BP5

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

BS1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4 linkuse as main transcript	c.3600C>G	p.Asp1200Glu	missense_variant	23/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8 linkuse as main transcript	c.3600C>G	p.Asp1200Glu	missense_variant	23/23	1	NM_005633.4	ENSP00000384675	A1	Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152104

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000159

AC:

AN:

251300

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.000343

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000252

AC:

368

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

152

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000323

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000138

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74412

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:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000994

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 21, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2019	This variant is associated with the following publications: (PMID: 27236105) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SOS1: BS1 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 02, 2023

Variant summary: SOS1 c.3600C>G (p.Asp1200Glu) results in a conservative amino acid change in 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 0.00016 in 251300 control chromosomes, predominantly at a frequency of 0.00034 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome phenotype (3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.3600C>G in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five other submitters, including an expert panel (ClinGen RASopathy Variant Curation Expert Panel), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=1), or likely benign (n=4; including the expert panel). Based on the evidence outlined above, the variant was classified as likely benign. -

SOS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 02, 2020

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). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 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. -

Noonan syndrome and Noonan-related syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen RASopathy Variant Curation Expert Panel

Jun 27, 2019

The c.3600C>G (p.Asp1200Glu) variant in the SOS1 gene has been identified in at least 6 individuals without detailed phenotypic information as well as one patient with an alternative molecular basis for disease in the BRAF gene (BP5; EGL, Invitae, GeneDx internal data, GTR Lab ID: 500060, 500031, 26957; SCV000854873.1, SCV000553268.3, SCV000209087.11). The filtering allele frequency of the c.3600C>G (p.Asp1200Glu) variant is 0.025% for European (non-Finnish) exomes by the gnomAD database (40/251300 with 95% CI) which is strong evidence to suggest that the variant may be benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BS1). Of note, the c.3600C>A change that also results in p.Asp1200Glu has been identified in one patient with a RASopathy but this variant has not met criteria to be classified as pathogenic and therefore PM5 is not met (Partners LMM internal data; GTR Lab ID: 21766; SCV000062231.5). Computational prediction tools and conservation analysis suggest that the p.Asp1200Glu variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP4, BP5. -

RASopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.9

DANN

Benign

0.74

DEOGEN2

Benign

0.37

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.69

.;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.046

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

0.85

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.68

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.86

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.015

MutPred

0.17

Gain of catalytic residue at D1200 (P = 0.0461);Gain of catalytic residue at D1200 (P = 0.0461);.;

MVP

0.40

MPC

0.093

ClinPred

0.044

GERP RS

-0.53

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.014

gMVP

0.087

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