rs367693130
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_005633.4(SOS1):c.3721A>G(p.Lys1241Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,624 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1241R) has been classified as Likely benign.
Frequency
Consequence
NM_005633.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.3721A>G | p.Lys1241Glu | missense_variant | 23/23 | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.3721A>G | p.Lys1241Glu | missense_variant | 23/23 | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151938Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251104Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135700
GnomAD4 exome AF: 0.0000629 AC: 92AN: 1461686Hom.: 0 Cov.: 32 AF XY: 0.0000578 AC XY: 42AN XY: 727140
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151938Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74184
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 26, 2009 | - - |
Noonan syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 21, 2020 | The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously reported as pathogenic or benign in relation to a Noonan-spectrum disorder to our knowledge; This variant is associated with the following publications: (PMID: 27418595) - |
Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 25, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2020 | The p.K1241E variant (also known as c.3721A>G), located in coding exon 23 of the SOS1 gene, results from an A to G substitution at nucleotide position 3721. The lysine at codon 1241 is replaced by glutamic acid, an amino acid with similar properties. This alteration was reported in an individual with tetralogy of Fallot (LaHaye S et al. Circ Cardiovasc Genet, 2016 Aug;9:320-9). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Fibromatosis, gingival, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | - | - - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1241 of the SOS1 protein (p.Lys1241Glu). This variant is present in population databases (rs367693130, gnomAD 0.002%). This missense change has been observed in individual(s) with tetralogy of Fallot (PMID: 27418595). ClinVar contains an entry for this variant (Variation ID: 45368). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SOS1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Noonan syndrome and Noonan-related syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at