rs766252091
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_001927.4(DES):c.937G>A(p.Ala313Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A313A) has been classified as Likely benign.
Frequency
Consequence
NM_001927.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.937G>A | p.Ala313Thr | missense_variant | 5/9 | ENST00000373960.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.937G>A | p.Ala313Thr | missense_variant | 5/9 | 1 | NM_001927.4 | P1 | |
DES | ENST00000477226.6 | n.411G>A | non_coding_transcript_exon_variant | 4/8 | 4 | ||||
DES | ENST00000492726.1 | n.332G>A | non_coding_transcript_exon_variant | 4/6 | 4 | ||||
DES | ENST00000683013.1 | n.325G>A | non_coding_transcript_exon_variant | 3/7 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 151968Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251026Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135704
GnomAD4 exome AF: 0.0000294 AC: 43AN: 1461646Hom.: 0 Cov.: 38 AF XY: 0.0000399 AC XY: 29AN XY: 727134
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152086Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2020 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 05, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 12, 2015 | The p.Ala313Thr variant in DES has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 3/66414 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In summary, the clinical significance of the p.Ala313Thr variant is uncertain. - |
Desmin-related myofibrillar myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 313 of the DES protein (p.Ala313Thr). This variant is present in population databases (rs766252091, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 228553). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES 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. - |
Dilated cardiomyopathy 1I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Nov 04, 2022 | The c.937G>A p.(Ala313Thr) variant identified in the DES gene has not previously been reported in the literature and has been deposited in ClinVar [ClinVar ID: 228553] as Variant of Uncertain Significance. The c.937G>A variant is observed in 9 alleles (~0.002% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.937G>A variant in DES is located in exon 5 of this 9-exon gene, and predicted to replace an evolutionarily conserved alanine amino acid with threonine at position 313 in the region of interaction with NEB of the encoded protein. In silico predictions are in favor of damaging effect for p.(Ala313Thr) [(CADD v1.6= 34, REVEL = 0.686)]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.937G>Ap.(Ala313Thr) variant identified in DES is classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 29, 2023 | The p.A313T variant (also known as c.937G>A), located in coding exon 5 of the DES gene, results from a G to A substitution at nucleotide position 937. The alanine at codon 313 is replaced by threonine, an amino acid with similar properties. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at