chr2-38986226-G-T
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_005633.4(SOS1):c.3600C>A(p.Asp1200Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1200T) 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 -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SOS1 | NM_005633.4 | c.3600C>A | p.Asp1200Glu | missense_variant | 23/23 | ENST00000402219.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SOS1 | ENST00000402219.8 | c.3600C>A | p.Asp1200Glu | missense_variant | 23/23 | 1 | NM_005633.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251300Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135802
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461674Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727136
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74286
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 | Feb 29, 2012 | Variant classified as Uncertain Significance - Favor Benign. The Asp1200Glu vari ant has not been reported in the literature nor previously identified by our lab oratory. Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) suggest that the Asp1200Glu variant may not i mpact the protein, though this information is not predictive enough to rule out pathogenicity. In addition, a different nucleotide substitution at this positio n (c.3600C>G) resulting in the same amino acid change has been identified in 0.0 3% (2/7020) of European American chromosomes from a broad population by the NHLB I Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; rs141594736). Alt hough this data supports that the Asp1200Glu variant may be benign, additional s tudies are needed to fully assess its clinical significance. - |
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 17, 2023 | This variant is present in population databases (rs141594736, gnomAD 0.004%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 45365). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1200 of the SOS1 protein (p.Asp1200Glu). - |
Noonan syndrome 4 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Noonan syndrome 4 (MIM#610733). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Due to ascertainment bias and variable expressivity with frequent subtlety of features, the penetrance of Noonan syndrome is difficult to determine; affected adults are often diagnosed only after the diagnosis of a more severely affected child (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). An alternative change at this nucleotide which results in the same change to glutamic acid has also been reported in gnomAD (v2) (44 heterozygotes, 0 homozygotes). (SP) 0309 - A few alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 11 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missene variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as a VUS once in ClinVar. Another change at this nucleotide which also results in a change to glutamic acid has been reported multiple times as likely benign in ClinVar. One of the submissions has a three star rating from FDA for Noonan syndrome. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at