rs201982464
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.3391+7A>G variant in the SOS1 gene is 0.193% (41/16108) of South Asian 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/CA136138/MONDO:0021060/004
Frequency
Consequence
NM_005633.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000618 AC: 94AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000715 AC: 179AN: 250474Hom.: 1 AF XY: 0.000842 AC XY: 114AN XY: 135376
GnomAD4 exome AF: 0.000668 AC: 957AN: 1433078Hom.: 1 Cov.: 26 AF XY: 0.000762 AC XY: 545AN XY: 714766
GnomAD4 genome AF: 0.000617 AC: 94AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74444
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:6
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SOS1: BS1 -
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Variant summary: The SOS1 c.3391+7A>G variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 94/118614 control chromosomes (1 homozygote) at a frequency of 0.0007925, which is approximately 26 times the estimated maximal expected allele frequency of a pathogenic SOS1 variant (0.00003), suggesting this variant is likely a benign polymorphism. Ths variant has been reported in affected individual and reported as a "disease-unrelated variant" by authors (Lepri_2011). In addition, multiple clinical diagnostic laboratories/reputable databases recently classified this variant as benign/VUS. Taken together, this variant is classified as benign. -
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not specified Benign:4
c.3391+7A>G in intron 21 of SOS1: This variant is not expected to have clinical significance because it is not located within the splice consensus sequence. It has been identified in 0.3% (41/16108) of South Asian chromosomes including one homozygous individual and 0.07% (45/65182) European chromosomes by the Exome Ag gregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs201982464). -
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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. -
RASopathy Benign:2
The filtering allele frequency of the c.3391+7A>G variant in the SOS1 gene is 0.193% (41/16108) of South Asian 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) -
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Noonan syndrome 4 Benign:1
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. -
Fibromatosis, gingival, 1 Benign:1
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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at