2-219421505-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The ENST00000373960.4(DES):c.1189G>A(p.Ala397Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,868 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A397S) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000373960.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.1189G>A | p.Ala397Thr | missense_variant | 6/9 | ENST00000373960.4 | NP_001918.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.1189G>A | p.Ala397Thr | missense_variant | 6/9 | 1 | NM_001927.4 | ENSP00000363071 | P1 | |
DES | ENST00000477226.6 | n.663G>A | non_coding_transcript_exon_variant | 5/8 | 4 | |||||
DES | ENST00000492726.1 | n.584G>A | non_coding_transcript_exon_variant | 5/6 | 4 | |||||
DES | ENST00000683013.1 | n.577G>A | non_coding_transcript_exon_variant | 4/7 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251402Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461868Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727238
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Desmin-related myofibrillar myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 17, 2023 | 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) 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. ClinVar contains an entry for this variant (Variation ID: 163028). This variant has not been reported in the literature in individuals affected with DES-related conditions. This variant is present in population databases (rs727502951, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 397 of the DES protein (p.Ala397Thr). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | The p.Ala397Thr variant in DES has been identified by our laboratory in 1 Cauca sian individual with educed ejection fraction, moderate mitral regurgitation, le ft atrial enlargement, first-frist degree atrioventricular block, left bundle-br anch block and muscle cramping/weakness. However, an additional pathogenic varia nt in LMNA was also identified in that individual. This variant has also been id entified in 1/16624 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Computational prediction tools and conse rvation analysis suggest that the p.Ala397Thr variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, the clinical significance of the p.Ala397Thr variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at