rs745868830
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BS2
The NM_004006.3(DMD):āc.821A>Gā(p.Tyr274Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000986 in 1,207,038 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y274Y) 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.821A>G | p.Tyr274Cys | missense_variant | 8/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.821A>G | p.Tyr274Cys | missense_variant | 8/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 14AN: 111677Hom.: 0 Cov.: 23 AF XY: 0.000177 AC XY: 6AN XY: 33877
GnomAD3 exomes AF: 0.000120 AC: 22AN: 182853Hom.: 0 AF XY: 0.000118 AC XY: 8AN XY: 67553
GnomAD4 exome AF: 0.0000959 AC: 105AN: 1095361Hom.: 0 Cov.: 29 AF XY: 0.0000748 AC XY: 27AN XY: 361095
GnomAD4 genome AF: 0.000125 AC: 14AN: 111677Hom.: 0 Cov.: 23 AF XY: 0.000177 AC XY: 6AN XY: 33877
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2021 | This variant is associated with the following publications: (PMID: 19937601) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 30, 2016 | - - |
Duchenne muscular dystrophy Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 25, 2019 | Variant summary: DMD c.821A>G (p.Tyr274Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 199695 control chromosomes including 11 hemizygotes. This frequency is not significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies (0.00013 vs 0.011). c.821A>G has been reported in the literature in individuals affected with Dystrophinopathies (Flanigan_2009, Luce_2019). One of the individuals was a male who carried another pathogenic DMD variant, c.3427dupC (p.Gln1143fsX34)(Luce_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evalution after 2014) cite the variant as uncertain significance and benign. Based on the evidence outlined above, the variant was classified as benign. - |
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 11, 2018 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 22, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at