rs727504641
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_005633.4(SOS1):c.1720G>A(p.Val574Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000428 in 1,613,566 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.1720G>A | p.Val574Ile | missense_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.1720G>A | p.Val574Ile | missense_variant | 10/23 | 1 | NM_005633.4 | ENSP00000384675 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 151990Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 250960Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135628
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461576Hom.: 1 Cov.: 31 AF XY: 0.0000454 AC XY: 33AN XY: 727104
GnomAD4 genome AF: 0.0000329 AC: 5AN: 151990Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74242
ClinVar
Submissions by phenotype
Noonan syndrome 4 Uncertain:2
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2016 | The V574I variant has not been published as a pathogenic or as a benign variant to our knowledge. The V574I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved in mammals. However, the V574I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense pathogenic variants in nearby residues have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 21, 2016 | Variant summary: The SOS1 c.1720G>A (p.Val574Ile) variant causes a missense change involving the alteration of a conserved nucleotide, which 4/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/121360 (1/30339), predominantly in the European (Non-Finnish) cohort, 4/66722 (1/16680), which exceeds the estimated maximal expected allele frequency for a pathogenic SOS1 variant of 1/33333, therefore, suggesting this variant is likely a benign polymorphism found primarily in population(s) of European (Non-Finnish) origin. However, this observation does not need to be cautiously considered since the cohort does harbor individuals that could have a SOS1 phenotype. A clinical diagnostic laboratory cites the variant as "uncertain significance." However, the variant has not been reported, to our knowledge, in affected individuals via publications. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Benign." - |
Fibromatosis, gingival, 1 Uncertain:2
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 24, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Val574Ile varia nt in SOS1 has not been previously identified by our laboratory, nor has it been reported in the literature. In addition, this variant is absent in large popula tion studies. Computational analyses (biochemical amino acid properties, conserv ation, AlignGVGD, PolyPhen2, and SIFT) suggest that the variant may not impact t he protein, though this information is not predictive enough to rule out pathoge nicity. In summary, additional information is needed to fully assess the clinica l significance of the Val574Ile variant. - |
Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations | Aug 29, 2023 | Heterozygous variant NM_005633:c.1720G>A (p.Val574Ile) in the SOS1 gene was found on WES data in female proband (52 y.o., Caucasian) with Brugada-like ECG, and family history burdened with oncology (no precise data about site and histology available). No additional rare candidate variants (Class III-V of pathogenicity) were found in this proband. This variant is in The Genome Aggregation Database (gnomAD) v2.1.1 with total MAF 0.00003985 (Date of access 29-08-2023). Clinvar contains entry for this variant (Variation ID: 179117). This variant has been reported on WES data in 1 patient with limb girdle muscular dystrophy (PMID: 29970176) and in prenatal cohort for genetic testing for Noonan syndrome (PMID: 29907801). Most in silico predictors show benign result of the protein change (varsome.com). In accordance with ACMG(2015) criteria this variant is classified as Variant of Uncertain Significance (VUS) wtih following criteria selected: BP4. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 29, 2024 | This 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. - |
RASopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 24, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at