X-32438341-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting
The NM_004006.3(DMD):c.3971G>A(p.Arg1324His) variant causes a missense change. The variant allele was found at a frequency of 0.0000124 in 1,209,476 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. 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. R1324C) has been classified as Likely benign.
Frequency
Consequence
NM_004006.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.3971G>A | p.Arg1324His | missense_variant | 29/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.3971G>A | p.Arg1324His | missense_variant | 29/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000269 AC: 3AN: 111703Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1AN XY: 33881
GnomAD3 exomes AF: 0.0000219 AC: 4AN: 182961Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67615
GnomAD4 exome AF: 0.0000109 AC: 12AN: 1097773Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2AN XY: 363215
GnomAD4 genome AF: 0.0000269 AC: 3AN: 111703Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1AN XY: 33881
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | DMD: PM2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; Identified in a patient with arrhythmogenic right ventricular cardiomyopathy, although zygosity of the variants was not provided. This individual also harbored a variant in another gene that may have also contributed to the phenotype (Forleo et al., 2017); This variant is associated with the following publications: (PMID: 31402444, 28750076) - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Apr 28, 2017 | p.Arg1324His (c.3971G>A) in exon 29 of the DMD gene (NM_004006.2) Given the lack of case data and lack of phenotype (HCM)-gene correlation, consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported in the literature in association with DMD-associated disease. The arginine at codon 1324 is conserved across species. Neighboring amino acids are not conserved., as are neighboring amino acids. Another variant at this amino acid, p. Arg1324Cys, is present in ClinVar and is classified as either a variant of uncertain significance, likely benign, or benign. The p.Arg1324Cys variant has a MAF of 0.7% in the gnomAD database. The variant was reported online in 4 of 122,674 individuals (all female) in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 2 of 26,545 chromosomes from people of Latino descent (MAF=0.007%), 1 of 79,777 chromosomes from people of European descent and 1 of 19,131 chromosomes from individuals of South Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. - |
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 28, 2018 | - - |
Duchenne muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 13, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1324 of the DMD protein (p.Arg1324His). This variant is present in population databases (rs768990357, gnomAD 0.008%). This missense change has been observed in individual(s) with arrythmogenic right ventricular cardiomyopathy (PMID: 28750076). ClinVar contains an entry for this variant (Variation ID: 455895). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at