rs142004123

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.2371C>A (p.Leu791Ile) variant in the SOS1 gene is 0.081% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (67/66688 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA136098/MONDO:0021060/004

Frequency

Genomes: đť‘“ 0.00053 ( 0 hom., cov: 32)
Exomes đť‘“: 0.00044 ( 1 hom. )

Consequence

SOS1
NM_005633.4 missense

Scores

1
5
13

Clinical Significance

Benign reviewed by expert panel U:2B:12

Conservation

PhyloP100: 3.30
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 Benign. Variant got -8 ACMG points.

BA1
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 linkc.2371C>A p.Leu791Ile missense_variant 14/23 ENST00000402219.8 NP_005624.2 Q07889-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SOS1ENST00000402219.8 linkc.2371C>A p.Leu791Ile missense_variant 14/231 NM_005633.4 ENSP00000384675.2 Q07889-1

Frequencies

GnomAD3 genomes
AF:
0.000532
AC:
81
AN:
152148
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000786
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000911
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000602
AC:
151
AN:
250972
Hom.:
0
AF XY:
0.000664
AC XY:
90
AN XY:
135630
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000752
Gnomad ASJ exome
AF:
0.0000994
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00102
Gnomad OTH exome
AF:
0.000653
GnomAD4 exome
AF:
0.000440
AC:
642
AN:
1459604
Hom.:
1
Cov.:
30
AF XY:
0.000438
AC XY:
318
AN XY:
726266
show subpopulations
Gnomad4 AFR exome
AF:
0.0000599
Gnomad4 AMR exome
AF:
0.000671
Gnomad4 ASJ exome
AF:
0.0000766
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000522
Gnomad4 OTH exome
AF:
0.000381
GnomAD4 genome
AF:
0.000532
AC:
81
AN:
152266
Hom.:
0
Cov.:
32
AF XY:
0.000524
AC XY:
39
AN XY:
74458
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.000785
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000912
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000768
Hom.:
2
Bravo
AF:
0.000484
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.000651
AC:
79
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00125
EpiControl
AF:
0.00166

ClinVar

Significance: Benign
Submissions summary: Uncertain:2Benign:12
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 17, 2018- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 05, 2017Variant summary: The SOS1 c.2371C>A (p.Leu791Ile) variant located in the Ras guanine nucleotide exchange factor domain (via InterPro) involves the alteration of a conserved nucleotide and 3/5 in silico tools predict a benign outcome for this variant. However, these predictions have yet to be functionally assessed. This variant was found in 153/276674 control chromosomes at a frequency of 0.000553, which is approximately 18 times the estimated maximal expected allele frequency of a pathogenic SOS1 variant (0.00003), suggesting this variant is likely a benign polymorphism. A publication, Lepri_2014, cites the variant in 2 individuals with limited information (ie, lack of cosegregation and/or co-occurrence data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 05, 2015proposed classification - variant undergoing re-assessment, contact laboratory -
not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024SOS1: BS1 -
Benign, criteria provided, single submitterclinical testingGeneDxJun 06, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Noonan syndrome Uncertain:1Benign:1
Uncertain significance, no assertion criteria providedclinical testingService de Génétique Moléculaire, Hôpital Robert Debré-- -
Benign, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalSep 23, 2020The c.2371C>A missense variant has a frequency of 0.0005737 (162 of 282,368 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.0009786 (126 of 128,756) in the European non-Finnish population (http://gnomad.broadinstitute.org). This is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BA1). In silico tools are not in agreement regarding the effect of this variant on protein function and functional assays have not been performed. This variant has been classified as benign by the ClinGen RASopathy Variant Curation Expert Panel (SCV000616439.3). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): BA1. -
RASopathy Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
Benign, reviewed by expert panelcurationClinGen RASopathy Variant Curation Expert PanelApr 03, 2017The filtering allele frequency of the c.2371C>A (p.Leu791Ile) variant in the SOS1 gene is 0.081% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (67/66688 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). -
Noonan syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 13, 2024This 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. -
Fibromatosis, gingival, 1 Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJun 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.45
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.38
T;T;T
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.95
.;D;D
M_CAP
Benign
0.0074
T
MetaRNN
Benign
0.098
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.030
N;N;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.6
N;N;N
REVEL
Benign
0.15
Sift
Benign
0.19
T;T;T
Sift4G
Benign
0.11
T;T;T
Polyphen
0.57
P;P;.
Vest4
0.28
MVP
0.38
MPC
1.0
ClinPred
0.041
T
GERP RS
5.9
Varity_R
0.48
gMVP
0.58

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: rs142004123; hg19: chr2-39239286; API