rs781748062
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_004006.3(DMD):c.8895T>A(p.Asp2965Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000579 in 1,208,630 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign 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. D2965N) has been classified as Likely benign.
Frequency
Consequence
NM_004006.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.8895T>A | p.Asp2965Glu | missense_variant | 59/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.8895T>A | p.Asp2965Glu | missense_variant | 59/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000269 AC: 3AN: 111326Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1AN XY: 33508
GnomAD3 exomes AF: 0.0000222 AC: 4AN: 179878Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 64616
GnomAD4 exome AF: 0.00000365 AC: 4AN: 1097304Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 362686
GnomAD4 genome ? AF: 0.0000269 AC: 3AN: 111326Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1AN XY: 33508
ClinVar
Submissions by phenotype
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 25, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 11, 2023 | - - |
Duchenne muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 2965 of the DMD protein (p.Asp2965Glu). This variant is present in population databases (rs781748062, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 455943). 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 DMD protein function with a negative predictive value of 95%. 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2021 | The p.D2965E variant (also known as c.8895T>A), located in coding exon 59 of the DMD gene, results from a T to A substitution at nucleotide position 8895. The aspartic acid at codon 2965 is replaced by glutamic acid, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.002% (4/179878) total alleles studied, with no hemizygotes observed. The highest observed frequency was 0.03% (4/12992) of African/African-American alleles. This amino acid position is highly conserved in available 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at