rs730881026

Variant summary

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

The ENST00000402219.8(SOS1):ā€‹c.3729C>Gā€‹(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: š‘“ 0.000072 ( 0 hom., cov: 32)
Exomes š‘“: 0.000073 ( 0 hom. )

Consequence

SOS1
ENST00000402219.8 missense

Scores

1
18

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]

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
SOS1NM_005633.4 linkuse as main transcriptc.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
SOS1ENST00000402219.8 linkuse as main transcriptc.3729C>G p.Asp1243Glu missense_variant 23/231 NM_005633.4 ENSP00000384675 A1Q07889-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152078
Hom.:
0
Cov.:
32
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:
8
AN:
251066
Hom.:
0
AF XY:
0.0000221
AC XY:
3
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.:
0
Cov.:
32
AF XY:
0.0000811
AC XY:
59
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:
11
AN:
152078
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
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.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000247
AC:
3
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 providedclinical testingPreventionGenetics, part of Exact SciencesMay 21, 2024The 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 submitterclinical testingAmbry GeneticsApr 12, 2022The 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 15, 2024Variant 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 submitterclinical testingGeneDxDec 29, 2020This variant is associated with the following publications: (PMID: 30050098, 29907801) -
Noonan syndrome and Noonan-related syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenDec 12, 2016- -
RASopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 28, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.48
T
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
D
LIST_S2
Benign
0.75
.;T;T
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.038
T;T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
-1.1
N;N;.
MutationTaster
Benign
0.96
N;N;N
PrimateAI
Uncertain
0.65
T
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
T
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.

Other links and lift over

dbSNP: rs730881026; hg19: chr2-39213238; API