Variant chr2-39054763-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005633.4(SOS1):c.571G>A(p.Glu191Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000567 in 1,586,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:9

Conservation

PhyloP100: 5.57

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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4 linkuse as main transcript	c.571G>A	p.Glu191Lys	missense_variant	5/23	ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8 linkuse as main transcript	c.571G>A	p.Glu191Lys	missense_variant	5/23	1	NM_005633.4	A1	Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000558

AC:

AN:

1434786

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

715574

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000644

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2024	Reported in a patient with dilated cardiomyopathy; however, this patient also harbored potentially disease-causing variants in other genes associated with cardiomyopathy (PMID: 32603605); De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29493581, 29437595, 32603605) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Noonan syndrome 4

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 29, 2023	This variant was identified in a patient with visual deficits and sysmorphic stigmata in line with the diagnosis of Noonan syndrome. The variant was present at low-level mosaicism (VAF 2%) in the blood DNA of the mother. Applying PS2, PM2 and PP5 the variant meets our criteria to be classified as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Noonan syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Oct 07, 2020

The c.571G>A missense variant has a frequency of 0.000006984 (1 of 143,180 alleles) with a maximum allele frequency of 0.00002380 (1 of 42,014) in the African subpopulation. This does not been criteria for PM2 based on ClinGen's RASopathy Expert Panel consensus methods for variant interpretation (PMID: 29493581). The p.Glu191Lys variant has been identified somatically in a patient with JMML (PMID: 29437595). The variant has also been found to segregate in a pedigree with aggressive, early-onset dilated cardiomyopathy alongside an A-band TTN truncating variant, and individuals without the SOS1 variant demonstrated reduced disease severity, thus suggesting this variant's potential involvement as a genetic risk factor for dilated cardiomyopathy in this family (PMID: 32603605). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3). In ERK activation studies, the p.Glu191Lys variant increased phosphorylated ERK expression relative to wild-type levels, paralleling known disease-relevant SOS1 signaling profiles (PS3; PMID: 32603605). In summary, the clinical significance of SOS1 c.571G>A (p.Glu191Lys) is uncertain based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): PS3, PP3. -

Primary dilated cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Fibromatosis, gingival, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

- -

RASopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 40656). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32603605). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 191 of the SOS1 protein (p.Glu191Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.57

D;D;T

Eigen

Uncertain

0.64

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

.;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.72

D;D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

1.9

L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.5

N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.22

T;T;T

Polyphen

0.99

D;D;.

Vest4

0.72

MutPred

0.33

Gain of ubiquitination at E191 (P = 0.0031);Gain of ubiquitination at E191 (P = 0.0031);Gain of ubiquitination at E191 (P = 0.0031);

MVP

0.88

MPC

1.3

ClinPred

0.88

GERP RS

5.9

Varity_R

0.27

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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