chr2-39035207-C-G

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.1074+5G>C variant in the SOS1 gene is 1.551% (837/50942) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA136073/MONDO:0021060/004

Frequency

Genomes: 𝑓 0.0063 ( 5 hom., cov: 32)
Exomes 𝑓: 0.0080 ( 56 hom. )

Consequence

SOS1
NM_005633.4 splice_region, intron

Scores

2
Splicing: ADA: 0.2881
2

Clinical Significance

Benign reviewed by expert panel B:20

Conservation

PhyloP100: 3.54
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 rank MANE Protein UniProt
SOS1NM_005633.4 linkc.1074+5G>C splice_region_variant, intron_variant Intron 8 of 22 ENST00000402219.8 NP_005624.2 Q07889-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SOS1ENST00000402219.8 linkc.1074+5G>C splice_region_variant, intron_variant Intron 8 of 22 1 NM_005633.4 ENSP00000384675.2 Q07889-1

Frequencies

GnomAD3 genomes
AF:
0.00632
AC:
961
AN:
151978
Hom.:
5
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00176
Gnomad AMI
AF:
0.00658
Gnomad AMR
AF:
0.00269
Gnomad ASJ
AF:
0.00634
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00664
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0109
Gnomad OTH
AF:
0.00288
GnomAD3 exomes
AF:
0.00668
AC:
1658
AN:
248288
Hom.:
8
AF XY:
0.00637
AC XY:
855
AN XY:
134232
show subpopulations
Gnomad AFR exome
AF:
0.00138
Gnomad AMR exome
AF:
0.00210
Gnomad ASJ exome
AF:
0.00528
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000199
Gnomad FIN exome
AF:
0.00751
Gnomad NFE exome
AF:
0.0117
Gnomad OTH exome
AF:
0.00495
GnomAD4 exome
AF:
0.00801
AC:
11569
AN:
1445048
Hom.:
56
Cov.:
29
AF XY:
0.00777
AC XY:
5590
AN XY:
719738
show subpopulations
Gnomad4 AFR exome
AF:
0.00118
Gnomad4 AMR exome
AF:
0.00220
Gnomad4 ASJ exome
AF:
0.00496
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000152
Gnomad4 FIN exome
AF:
0.00714
Gnomad4 NFE exome
AF:
0.00961
Gnomad4 OTH exome
AF:
0.00602
GnomAD4 genome
AF:
0.00632
AC:
961
AN:
152096
Hom.:
5
Cov.:
32
AF XY:
0.00589
AC XY:
438
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00176
Gnomad4 AMR
AF:
0.00268
Gnomad4 ASJ
AF:
0.00634
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00664
Gnomad4 NFE
AF:
0.0109
Gnomad4 OTH
AF:
0.00285
Alfa
AF:
0.00985
Hom.:
2
Bravo
AF:
0.00563

ClinVar

Significance: Benign
Submissions summary: Benign:20
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:7
Mar 25, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

1074+5G>C in intron 8 of SOS1: This variant has not been previously reported in the literature. However, this variant has been identified in 12/1154 (1%) of ind ividual's tested by our laboratory, two of whom have a pathogenic variant in PTP N11. In addition, this variant is located in the 5' splice region but does not a ffect the highly conserved +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions s ometimes affect splicing. This type of variant has not been previously reported as pathogenic in SOS1. Therefore, this variant is likely to be benign. -

Jan 15, 2015
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 22, 2013
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 01, 2010
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 19, 2011
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This 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. -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:6
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SOS1: BP4, BS1, BS2 -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 04, 2023
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Apr 21, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

RASopathy Benign:2
Apr 18, 2017
ClinGen RASopathy Variant Curation Expert Panel
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: curation

The filtering allele frequency of the c.1074+5G>C variant in the SOS1 gene is 1.551% (837/50942) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) -

Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Noonan syndrome 4 Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Benign:1
Oct 08, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
May 13, 2016
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Noonan syndrome and Noonan-related syndrome Benign:1
May 28, 2021
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.27
CADD
Benign
22
DANN
Benign
0.96
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.2

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.29
dbscSNV1_RF
Benign
0.44
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: rs145155424; hg19: chr2-39262348; API