rs144757941
Variant summary
Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2
The NM_005633.4(SOS1):c.280A>G(p.Ile94Val) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,612,358 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I94T) has been classified as Uncertain significance.
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.280A>G | p.Ile94Val | missense_variant | 3/23 | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.280A>G | p.Ile94Val | missense_variant | 3/23 | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250990Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135668
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460248Hom.: 0 Cov.: 29 AF XY: 0.00000826 AC XY: 6AN XY: 726504
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74298
ClinVar
Submissions by phenotype
Noonan syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 22, 2020 | The c.280A>G missense variant has a frequency of 0.0005213 (13 of 24,938 alleles) in the African subpopulation in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel for autosomal dominant RASopathy variants (BS1). In silico tools are not in agreement regarding the effect of this variant on protein function and functional assays have not been performed. This variant has been classified as likely benign by the ClinGen RASopathy Variant Curation Expert Panel (SCV000616526.3). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria, as specified by the ClinGen RASopathy Variant Curation Expert Panel (PMID:29493581): BS1. - |
Uncertain significance, no assertion criteria provided | clinical testing | Service de Génétique Moléculaire, Hôpital Robert Debré | - | - - |
RASopathy Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 17, 2023 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 18, 2017 | The filtering allele frequency of the c.280A>G (p.Ile94Val) variant in the SOS1 gene is 0.0253% (6/10300) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581) - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2020 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 05, 2019 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at