rs3827462
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_004006.3(DMD):c.3406A>T(p.Thr1136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00612 in 1,206,084 control chromosomes in the GnomAD database, including 147 homozygotes. There are 3,123 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.
Frequency
Consequence
NM_004006.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.3406A>T | p.Thr1136Ser | missense_variant | 25/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.3406A>T | p.Thr1136Ser | missense_variant | 25/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00502 AC: 559AN: 111447Hom.: 6 Cov.: 23 AF XY: 0.00755 AC XY: 254AN XY: 33637
GnomAD3 exomes AF: 0.0116 AC: 2044AN: 175573Hom.: 29 AF XY: 0.0144 AC XY: 877AN XY: 60789
GnomAD4 exome AF: 0.00623 AC: 6823AN: 1094585Hom.: 141 Cov.: 29 AF XY: 0.00796 AC XY: 2868AN XY: 360407
GnomAD4 genome ? AF: 0.00503 AC: 561AN: 111499Hom.: 6 Cov.: 23 AF XY: 0.00757 AC XY: 255AN XY: 33699
ClinVar
Submissions by phenotype
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 04, 2015 | p.Thr1136Ser in exon 25 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 7% (451/6490) of South Asian chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3827462). - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 03, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 07, 2021 | Variant summary: DMD c.3406A>T (p.Thr1136Ser) results in a conservative amino acid change located in the Central rod domain (Repeat 7) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.012 in 175573 control chromosomes, predominantly at a frequency of 0.05 within the South Asian subpopulation in the gnomAD database, including 18 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4533 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 South Asian origin. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as benign (n=4) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 07, 2014 | 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. - |
Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 21, 2017 | - - |
Dilated cardiomyopathy 3B Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 10, 2019 | - - |
Primary dilated cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Mar 11, 2015 | - - |
Duchenne muscular dystrophy Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 24, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at