chrX-32644145-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_004006.3(DMD):c.1318G>A(p.Glu440Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,205,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 59 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). Synonymous variant affecting the same amino acid position (i.e. E440E) 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.1318G>A | p.Glu440Lys | missense_variant | 11/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.1318G>A | p.Glu440Lys | missense_variant | 11/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000206 AC: 23AN: 111526Hom.: 0 Cov.: 23 AF XY: 0.000237 AC XY: 8AN XY: 33724
GnomAD3 exomes AF: 0.000470 AC: 84AN: 178649Hom.: 0 AF XY: 0.000393 AC XY: 25AN XY: 63585
GnomAD4 exome AF: 0.000160 AC: 175AN: 1093785Hom.: 0 Cov.: 29 AF XY: 0.000145 AC XY: 52AN XY: 359683
GnomAD4 genome ? AF: 0.000197 AC: 22AN: 111578Hom.: 0 Cov.: 23 AF XY: 0.000207 AC XY: 7AN XY: 33786
ClinVar
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2019 | Variant summary: DMD c.1318G>A (p.Glu440Lys) results in a conservative amino acid change located in the Spectrin/alpha-actinin repeat of 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 0.00043 in 195664 control chromosomes, predominantly at a frequency of 0.0053 within the East Asian subpopulation in the gnomAD database, including 24 hemizygotes. This frequency is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies, strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1318G>A has been reported in the literature in a family affected with Becker muscular dystrophy and it was found in cis with a pathogenic variant (DMD deletion of exons 45 to 53) in 3 affected males and 2 female carriers (Li_2012), 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 (evaluation after 2014) cite the variant as benign and a submission derived from reference population cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 21, 2016 | - - |
Becker muscular dystrophy Uncertain:2
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Duchenne muscular dystrophy Benign:2
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Dystrophin deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 23, 2020 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | May 20, 2014 | The variant is found in CARDIOMYOPATHY panel(s). - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 24, 2019 | This alteration is classified as likely 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