rs775192483
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_003036.4(SKI):c.919G>A(p.Val307Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,602,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V307V) has been classified as Likely benign.
Frequency
Consequence
NM_003036.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SKI | NM_003036.4 | c.919G>A | p.Val307Met | missense_variant | 1/7 | ENST00000378536.5 | |
SKI | XM_005244775.4 | c.919G>A | p.Val307Met | missense_variant | 1/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SKI | ENST00000378536.5 | c.919G>A | p.Val307Met | missense_variant | 1/7 | 1 | NM_003036.4 | P1 | |
SKI | ENST00000704337.1 | n.137+2161G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000136 AC: 3AN: 221068Hom.: 0 AF XY: 0.0000247 AC XY: 3AN XY: 121654
GnomAD4 exome AF: 0.0000207 AC: 30AN: 1450002Hom.: 0 Cov.: 33 AF XY: 0.0000208 AC XY: 15AN XY: 720782
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152264Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74382
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2022 | The p.V307M variant (also known as c.919G>A), located in coding exon 1 of the SKI gene, results from a G to A substitution at nucleotide position 919. The valine at codon 307 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and methionine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 17, 2015 | p.Val307Met (V307M) GTG>ATG: c.919 G>A in exon 1 of the SKI gene (NM_003036.3) A variant of unknown significance has been identified in the SKI gene. The V307M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The V307M variant was not observed in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The V307M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species, including Methionine which is present as the wild type in several species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, no missense mutations in nearby residues have been reported in association with SKI-related disorders, suggesting this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-1 - |
Shprintzen-Goldberg syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 23, 2022 | This variant is present in population databases (rs775192483, 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 SKI protein function. ClinVar contains an entry for this variant (Variation ID: 213686). This variant has not been reported in the literature in individuals affected with SKI-related conditions. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 307 of the SKI protein (p.Val307Met). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at