rs201217593
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_004006.3(DMD):c.10247G>A(p.Trp3416Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,206,155 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004006.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.10247G>A | p.Trp3416Ter | stop_gained | 71/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.10247G>A | p.Trp3416Ter | stop_gained | 71/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000360 AC: 4AN: 110979Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1AN XY: 33301
GnomAD3 exomes AF: 0.0000223 AC: 4AN: 179286Hom.: 0 AF XY: 0.0000155 AC XY: 1AN XY: 64508
GnomAD4 exome AF: 0.00000183 AC: 2AN: 1095176Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 360836
GnomAD4 genome ? AF: 0.0000360 AC: 4AN: 110979Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1AN XY: 33301
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Oct 17, 2022 | PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2022 | Reported as a heterozygous variant in a patient with atherosclerosis in published literature; however, additional clinical information was not provided (Johnston et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Based on the understanding of this genetic alteration, it may be amenable to nonsense read-through therapy that is currently available or in clinical trial; This variant is associated with the following publications: (PMID: 26046366) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 29, 2022 | - - |
Qualitative or quantitative defects of dystrophin Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2023 | Variant summary: DMD c.10247G>A (p.Trp3416X) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 2.2e-05 in 179286 control chromosomes (gnomAD) to include at-least one hemizygous individual with an unknown clinical history. To our knowledge, c.10247G>A has not been reported in the literature in individuals affected with Dystrophinopathies and no experimental evidence demonstrating an impact on protein function has been reported. However, it has been reported in at-least one individual with a negative personal/family history for muscle disease as part of the ClinSeq cohort that were selected for atherosclerosis but not for personal or family histories of any other phenotype (Johnston_2015). The following publication have been ascertained in the context of this evaluation (PMID: 26046366). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=3) and pathogenic/likely pathogenic (n= 4). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Becker muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 21, 2023 | - - |
Ptosis;C0015300:Proptosis;C0878544:Cardiomyopathy;C1850049:Clinodactyly of the 5th finger;C2051831:Pectus excavatum Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 03, 2014 | - - |
Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 16, 2021 | The p.W3416* pathogenic mutation (also known as c.10247G>A), located in coding exon 71 of the DMD gene, results from a G to A substitution at nucleotide position 10247. This changes the amino acid from a tryptophan to a stop codon within coding exon 71. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Duchenne muscular dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Trp3416*) in the DMD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). In addition, truncating variants in exon 71 (p.Pro3409Tyr*22, p.Thr3411Asn*22, and p.Leu3412Argfs*7) that result in partial in-frame exon skipping have been observed in individuals with clinical features of mild Becker muscular dystrophy (PMID: 17041906, 23536893). This variant is present in population databases (rs201217593, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 374132). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at