18-49044186-AT-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong
The NM_001353214.3(DYM):c.2043delA(p.Lys681AsnfsTer94) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001353214.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DYM | NM_001353214.3 | c.2043delA | p.Lys681AsnfsTer94 | frameshift_variant | Exon 18 of 18 | ENST00000675505.1 | NP_001340143.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DYM | ENST00000675505.1 | c.2043delA | p.Lys681AsnfsTer94 | frameshift_variant | Exon 18 of 18 | NM_001353214.3 | ENSP00000501694.1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 13AN: 152186Hom.: 0 Cov.: 33 FAILED QC
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251368Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135874
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727242
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000854 AC: 13AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8AN XY: 74344
ClinVar
Submissions by phenotype
Dyggve-Melchior-Clausen syndrome Pathogenic:3
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The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). Frameshift: predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 12554689). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided Pathogenic:1
This sequence change results in a frameshift in the DYM gene (p.Lys626Asnfs*94). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 44 amino acid(s) of the DYM protein and extend the protein by 49 additional amino acid residues. This variant is present in population databases (no rsID available, gnomAD 0.02%). This frameshift has been observed in individuals with clinical features of Dyggve-Melchior-Clausen disease (PMID: 12554689, 22090722; Invitae). This variant is also known as c.1877delA. ClinVar contains an entry for this variant (Variation ID: 3191). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at