X-32362931-G-A
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_004006.3(DMD):c.5182C>T(p.Arg1728Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000549 in 1,208,526 control chromosomes in the GnomAD database, including 5 homozygotes. There are 181 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1728H) has been classified as Likely benign.
Frequency
Consequence
NM_004006.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.5182C>T | p.Arg1728Cys | missense_variant | 37/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.5182C>T | p.Arg1728Cys | missense_variant | 37/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00294 AC: 327AN: 111055Hom.: 3 Cov.: 22 AF XY: 0.00289 AC XY: 96AN XY: 33263
GnomAD3 exomes AF: 0.000776 AC: 141AN: 181795Hom.: 0 AF XY: 0.000376 AC XY: 25AN XY: 66469
GnomAD4 exome AF: 0.000306 AC: 336AN: 1097414Hom.: 2 Cov.: 31 AF XY: 0.000234 AC XY: 85AN XY: 362854
GnomAD4 genome ? AF: 0.00295 AC: 328AN: 111112Hom.: 3 Cov.: 22 AF XY: 0.00288 AC XY: 96AN XY: 33330
ClinVar
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 10, 2017 | p.Arg1728Cys in exon 37 of DMD: This variant is classified as benign because it has been identified in 0.9% (180/18042) of African chromosomes, including 48 hem izygotes and 1 homozygote, by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org; dbSNP rs34102501). - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 17, 2015 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2019 | Variant summary: DMD c.5182C>T (p.Arg1728Cys) results in a non-conservative amino acid change located in the central rod domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 203656 control chromosomes, predominantly at a frequency of 0.0097 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 880 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathies phenotype (1.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as benign (5x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign. - |
not provided Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Aug 28, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 09, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 01, 2017 | - - |
Dilated cardiomyopathy 3B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 09, 2017 | - - |
DMD-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 10, 2019 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Duchenne muscular dystrophy Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at