rs201352584

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_005633.4(SOS1):ā€‹c.233T>Gā€‹(p.Phe78Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,612,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.00017 ( 0 hom., cov: 32)
Exomes š‘“: 0.00012 ( 0 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

15
3
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 9.20
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 -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.89
BP6
Variant 2-39058785-A-C is Benign according to our data. Variant chr2-39058785-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 40646.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=7, Benign=1}. Variant chr2-39058785-A-C is described in Lovd as [Benign].
BS2
High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SOS1NM_005633.4 linkuse as main transcriptc.233T>G p.Phe78Cys missense_variant 3/23 ENST00000402219.8 NP_005624.2 Q07889-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SOS1ENST00000402219.8 linkuse as main transcriptc.233T>G p.Phe78Cys missense_variant 3/231 NM_005633.4 ENSP00000384675.2 Q07889-1

Frequencies

GnomAD3 genomes
AF:
0.000171
AC:
26
AN:
152124
Hom.:
0
Cov.:
32
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:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000324
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000116
AC:
29
AN:
250656
Hom.:
0
AF XY:
0.000111
AC XY:
15
AN XY:
135582
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.000277
Gnomad NFE exome
AF:
0.000203
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000124
AC:
181
AN:
1460272
Hom.:
0
Cov.:
29
AF XY:
0.000113
AC XY:
82
AN XY:
726484
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:
0.000206
Gnomad4 NFE exome
AF:
0.000145
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152124
Hom.:
0
Cov.:
32
AF XY:
0.000242
AC XY:
18
AN XY:
74294
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:
0.000188
Gnomad4 NFE
AF:
0.000324
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000218
Hom.:
0
Bravo
AF:
0.000110
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000218
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024SOS1: PP3 -
Benign, criteria provided, single submitterclinical testingGeneDxSep 24, 2018This variant is associated with the following publications: (PMID: 24939586, 17586837, 21387466) -
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsMay 30, 2017- -
Noonan syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Noonan syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingNew York Genome CenterDec 01, 2021The c.233T>G (p.Phe78Cys) variant identified in the SOS1 gene substitues a Phenylalnine for Cysteine at amino acid 78/1334 (coding exon 2/23). It is identified in gnomAD (44 heterozygotes, 0 homozygotes; allele frequency 1.56e-4) and ExAC (15 heterozygotes, 0 homozygotes; allele frequency: 1.24e-4. In silico algorithms predict this variant will be Deleterious (Provean; Score: -7.01) and Damaging (SIFT;Score: 0.00) to the function of the canonical transcript. The c.233T>G (p.Phe78Cys) variant is reported in ClinVar as a Variant of Uncertain Significance (VarID:40646), and has been described in two individuals in the literature who met clinical criteriafor Noonan syndrome [doi:10.4183/aeb.2014.463; PMID: 17586837], one of which was inherited from a presumably unaffected parent [PMID: 17586837]. Given the lack of compelling information supporting the pathogenicity of the c.233T>G (p.Phe78Cys) variant identified in this indivudal, it is reported here as a Variant of Uncertain Significance. -
SOS1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesMar 01, 2023The SOS1 c.233T>G variant is predicted to result in the amino acid substitution p.Phe78Cys. This variant was reported in a patient with Noonan syndrome as well as their mother who was said to be clinically unaffected but was not available for phenotypic examination (Zenker et al. 2007. PubMed ID: 17586837). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-39285926-A-C), which is likely to high to be a primary cause of disease (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. -
Ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Advanced Laboratory Medicine, UC San Diego Health, University of California San DiegoJan 31, 2019- -
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 78 of the SOS1 protein (p.Phe78Cys). This variant is present in population databases (rs201352584, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with SOS1-related conditions (PMID: 17586837). ClinVar contains an entry for this variant (Variation ID: 40646). 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) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function with a positive predictive value of 95%. 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. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 21, 2022This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;D;T;T
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
.;D;D;D
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.89
D;D;D;D
MetaSVM
Uncertain
0.76
D
MutationAssessor
Pathogenic
2.9
M;M;.;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-7.1
D;D;D;D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;.
Polyphen
1.0
D;D;.;.
Vest4
0.97
MVP
0.98
MPC
1.8
ClinPred
0.89
D
GERP RS
5.6
Varity_R
0.95
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs201352584; hg19: chr2-39285926; COSMIC: COSV105933681; API