rs141390073
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Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BA1BP4BP7BP5
This summary comes from the ClinGen Evidence Repository: The c.1230G>A variant in the SOS1 gene is a synonymous (silent) variant (p.Gln410=) at a nucleotide that is not highly conserved and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v4.1.0 is 4.078% (2165/59926 alleles, 47 homozygotes) in the Admixed American population and therefore meets BA1. This variant has been identified in patients with an alternate molecular basis for disease (BP5; Partners LMM internal data GTR Lab ID: 21766, ClinVar SCV000062189.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5, BP7 (Specification Version 2.1, 09/17/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA136077/MONDO:0021060/041
Frequency
Genomes: 𝑓 0.0023 ( 5 hom., cov: 32)
Exomes 𝑓: 0.0018 ( 51 hom. )
Consequence
SOS1
ENST00000402219.8 synonymous
ENST00000402219.8 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.0360
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 -11 ACMG points.
BP4
For more information check the summary or visit ClinGen Evidence Repository.
BP5
For more information check the summary or visit ClinGen Evidence Repository.
BP7
For more information check the summary or visit ClinGen Evidence Repository.
BA1
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SOS1 | NM_005633.4 | c.1230G>A | p.Gln410= | synonymous_variant | 10/23 | ENST00000402219.8 | NP_005624.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SOS1 | ENST00000402219.8 | c.1230G>A | p.Gln410= | synonymous_variant | 10/23 | 1 | NM_005633.4 | ENSP00000384675 | A1 |
Frequencies
GnomAD3 genomes 0.00234 AC: 355AN: 151974Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00749 AC: 1872AN: 250082Hom.: 37 AF XY: 0.00584 AC XY: 790AN XY: 135280
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GnomAD4 exome AF: 0.00182 AC: 2664AN: 1460962Hom.: 51 Cov.: 31 AF XY: 0.00161 AC XY: 1173AN XY: 726784
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GnomAD4 genome 0.00235 AC: 357AN: 152092Hom.: 5 Cov.: 32 AF XY: 0.00269 AC XY: 200AN XY: 74386
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ClinVar
Significance: Benign
Submissions summary: Uncertain:1Benign:12
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
| Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jan 15, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 07, 2010 | Changed to benign since variant has been observed in two individuals with other known pathogenic variants in PTPN11. - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 17, 2014 | - - |
RASopathy Benign:2
| Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Sep 17, 2024 | The c.1230G>A variant in the SOS1 gene is a synonymous (silent) variant (p.Gln410=) at a nucleotide that is not highly conserved and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v4.1.0 is 4.078% (2165/59926 alleles, 47 homozygotes) in the Admixed American population and therefore meets BA1. This variant has been identified in patients with an alternate molecular basis for disease (BP5; Partners LMM internal data GTR Lab ID: 21766, ClinVar SCV000062189.6). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP5, BP7 (Specification Version 2.1, 09/17/2024) - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Noonan syndrome 4 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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 Benign:1
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 25, 2018 | - - |
Cardiovascular phenotype Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 01, 2016 | 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
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | 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
| Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 28, 2021 | - - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at