chr2-38986097-G-C

Position:

chr2-38986097-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The ENST00000402219.8(SOS1):c.3729C>G(p.Asp1243Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000725 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

SOS1
ENST00000402219.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.159

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 -5 ACMG points.

BP6

Variant 2-38986097-G-C is Benign according to our data. Variant chr2-38986097-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 40734.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr2-38986097-G-C is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4 linkuse as main transcript	c.3729C>G	p.Asp1243Glu	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.3729C>G	p.Asp1243Glu	missense_variant	23/23	1	NM_005633.4	ENSP00000384675	A1	Q07889-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152078

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:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

251066

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135670

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461680

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000845

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74280

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:

0.000147

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000251

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

SOS1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2024

The SOS1 c.3729C>G variant is predicted to result in the amino acid substitution p.Asp1243Glu. This variant has been reported in a fetus with cystic hygroma; however, the authors suspected the variant was possibly benign (Table S2, Leach et al. 2019. PubMed ID: 29907801). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too common to be pathogenic (Gelb et al. 2018. PubMed ID 29493581). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The p.D1243E variant (also known as c.3729C>G), located in coding exon 23 of the SOS1 gene, results from a C to G substitution at nucleotide position 3729. The aspartic acid at codon 1243 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in a prenatal subject with cystic hygroma (Leach NT et al. Genet Med, 2019 02;21:417-425). This amino acid position is not well conserved in available vertebrate species, and glutamic acid is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 15, 2024

Variant summary: SOS1 c.3729C>G (p.Asp1243Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 1613758 control chromosomes (gnomAD). The observed variant frequency is approximately 2.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome And Related Conditions phenotype (3e-05), strongly suggesting that the variant is benign. c.3729C>G has been reported in the literature in a prenatal sample with cystic hygroma without strong evidence for causality (Leach_2019). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29907801). ClinVar contains an entry for this variant (Variation ID: 40734). Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2020

This variant is associated with the following publications: (PMID: 30050098, 29907801) -

Noonan syndrome and Noonan-related syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

RASopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.61

CADD

Benign

5.7

DANN

Benign

0.22

DEOGEN2

Benign

0.33

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.75

.;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.038

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.1

N;N;.

MutationTaster

Benign

0.96

N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.40

N;N;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.015

MutPred

0.15

Gain of glycosylation at K1241 (P = 0.1473);Gain of glycosylation at K1241 (P = 0.1473);.;

MVP

0.37

MPC

0.092

ClinPred

0.014

GERP RS

-5.3

Varity_R

0.021

gMVP

0.033

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: 5

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