rs373319212
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_005633.4(SOS1):c.3357C>T(p.Thr1119Thr) variant causes a synonymous change. The variant allele was found at a frequency of 0.0000654 in 1,604,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_005633.4 synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 151930Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000639 AC: 16AN: 250202Hom.: 0 AF XY: 0.0000813 AC XY: 11AN XY: 135262
GnomAD4 exome AF: 0.0000606 AC: 88AN: 1452514Hom.: 0 Cov.: 27 AF XY: 0.0000650 AC XY: 47AN XY: 723112
GnomAD4 genome AF: 0.000112 AC: 17AN: 151930Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74190
ClinVar
Submissions by phenotype
not provided Benign:3
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Variant summary: The SOS1 c.3357C>T (p.Thr1119Thr) variant causes a synonymous change involving a conserved nucleotide with 5/5 splice prediction tools predicting no significant effect on splicing and ESE finder predicting that this variant may create a new affect ESE site of, although these predictions have yet to be functionally assessed. This variant was observed in the large, broad control population, ExAC, with an allele frequency of 9/118630 (1/13175, frequency: 0.0000759), predominantly in the European (Non-Finnish) cohort, 8/65198 (1/8149), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic SOS1 variant of 1/33333 (0.00003). Therefore, suggesting that the variant is a common polymorphism found in population(s) of European (Non-Finnish) origin. A publication cites the variant to have been found in at least one affected individual, although with limited information (ie lack of co-occurrence cosegregation data). In addition, a reputable clinical laboratory cites the variant as "likely benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
not specified Benign:1
p.Thr1119Thr in exon 21 of SOS1: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 8/65198 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs373319212). -
Noonan syndrome 4 Benign:1
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Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Benign:1
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Cardiovascular phenotype Benign:1
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. -
Fibromatosis, gingival, 1 Benign:1
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RASopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at