rs397517171

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005633.4(SOS1):​c.3952T>A​(p.Ser1318Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1318C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SOS1
NM_005633.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.58
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12342343).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOS1NM_005633.4 linkuse as main transcriptc.3952T>A p.Ser1318Thr missense_variant 23/23 ENST00000402219.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOS1ENST00000402219.8 linkuse as main transcriptc.3952T>A p.Ser1318Thr missense_variant 23/231 NM_005633.4 A1Q07889-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 11, 2009- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 02, 2022Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29493581) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.070
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
18
DANN
Benign
0.91
DEOGEN2
Benign
0.31
T;T;T
Eigen
Benign
-0.23
Eigen_PC
Benign
-0.11
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.83
.;T;T
M_CAP
Benign
0.034
D
MetaRNN
Benign
0.12
T;T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
1.0
L;L;.
MutationTaster
Benign
0.95
D;D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Benign
0.10
N;N;N
REVEL
Benign
0.26
Sift
Benign
0.18
T;T;T
Sift4G
Benign
0.97
T;T;T
Polyphen
0.0050
B;B;.
Vest4
0.25
MutPred
0.081
Gain of glycosylation at S1318 (P = 0.0095);Gain of glycosylation at S1318 (P = 0.0095);.;
MVP
0.48
MPC
0.40
ClinPred
0.44
T
GERP RS
2.5
Varity_R
0.048
gMVP
0.12

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.

Other links and lift over

dbSNP: rs397517171; hg19: chr2-39213015; API