rs200794965

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.2156G>C (p.Gly719Ala) variant in the SOS1 gene is 0.0414% (37/66598) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA297202/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

SOS1
ENST00000402219.8 missense

Scores

2
17

Clinical Significance

Likely benign reviewed by expert panel U:1B:6

Conservation

PhyloP100: 3.28
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 Likely_benign. Variant got -4 ACMG points.

BS1
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SOS1NM_005633.4 linkuse as main transcriptc.2156G>C p.Gly719Ala missense_variant 13/23 ENST00000402219.8 NP_005624.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SOS1ENST00000402219.8 linkuse as main transcriptc.2156G>C p.Gly719Ala missense_variant 13/231 NM_005633.4 ENSP00000384675 A1Q07889-1

Frequencies

GnomAD3 genomes
AF:
0.0000396
AC:
6
AN:
151686
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000657
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:
0.0000589
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000187
AC:
47
AN:
250736
Hom.:
0
AF XY:
0.000214
AC XY:
29
AN XY:
135502
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.000380
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000902
AC:
131
AN:
1452508
Hom.:
0
Cov.:
30
AF XY:
0.0000940
AC XY:
68
AN XY:
723312
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.000206
Gnomad4 NFE exome
AF:
0.0000988
Gnomad4 OTH exome
AF:
0.000133
GnomAD4 genome
AF:
0.0000396
AC:
6
AN:
151686
Hom.:
0
Cov.:
32
AF XY:
0.0000405
AC XY:
3
AN XY:
74082
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.0000657
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000589
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000546
Hom.:
0
Bravo
AF:
0.0000302
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.000305
AC:
37
EpiCase
AF:
0.000218
EpiControl
AF:
0.000119

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:1Benign:6
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 30, 2021- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 01, 2021This variant is associated with the following publications: (PMID: 32603605) -
RASopathy Benign:2
Likely benign, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelApr 18, 2017The filtering allele frequency of the c.2156G>C (p.Gly719Ala) variant in the SOS1 gene is 0.0414% (37/66598) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 08, 2024- -
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria providedresearchUniversity of Washington Center for Mendelian Genomics, University of Washington-- -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 09, 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. -
Noonan syndrome and Noonan-related syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenNov 01, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.087
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.58
CADD
Benign
19
DANN
Benign
0.95
DEOGEN2
Benign
0.36
T;T;T
Eigen
Benign
-0.17
Eigen_PC
Benign
0.091
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.74
.;T;T
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.095
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.29
N;N;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.18
N;N;N
REVEL
Benign
0.10
Sift
Benign
0.36
T;T;T
Sift4G
Benign
0.27
T;T;T
Polyphen
0.0
B;B;.
Vest4
0.23
MutPred
0.34
Gain of MoRF binding (P = 0.121);Gain of MoRF binding (P = 0.121);Gain of MoRF binding (P = 0.121);
MVP
0.22
MPC
0.61
ClinPred
0.069
T
GERP RS
5.9
Varity_R
0.22
gMVP
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs200794965; hg19: chr2-39240612; API