chrX-32380626-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004006.3(DMD):c.4729C>T(p.Arg1577Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Consequence
DMD
NM_004006.3 stop_gained
NM_004006.3 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 1.43
Genes affected
DMD (HGNC:2928): (dystrophin) This gene spans a genomic range of greater than 2 Mb and encodes a large protein containing an N-terminal actin-binding domain and multiple spectrin repeats. The encoded protein forms a component of the dystrophin-glycoprotein complex (DGC), which bridges the inner cytoskeleton and the extracellular matrix. Deletions, duplications, and point mutations at this gene locus may cause Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), or cardiomyopathy. Alternative promoter usage and alternative splicing result in numerous distinct transcript variants and protein isoforms for this gene. [provided by RefSeq, Dec 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-32380626-G-A is Pathogenic according to our data. Variant chrX-32380626-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 217199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32380626-G-A is described in Lovd as [Pathogenic]. Variant chrX-32380626-G-A is described in Lovd as [Benign]. Variant chrX-32380626-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.4729C>T | p.Arg1577Ter | stop_gained | 34/79 | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.4729C>T | p.Arg1577Ter | stop_gained | 34/79 | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 genomes
Cov.:
22
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome Cov.: 22
GnomAD4 genome
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 28, 2020 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 22, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 05, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 09, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in 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: 19783145, 21515508, 21972111, 28503591, 12233050, 20485447, 19937601, 25525159, 23453023, 18652600, 26110187, 28332368, 28318817, 31412794, 32559196, 34297739, 34925456) - |
Duchenne muscular dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 26, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 217199). This premature translational stop signal has been observed in individuals with Duchenne muscular dystrophy (PMID: 18652600, 19783145, 20485447, 21515508, 23453023). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1577*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Dec 16, 2022 | PVS1, PM2, PP5 - |
Qualitative or quantitative defects of dystrophin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2019 | Variant summary: DMD c.4729C>T (p.Arg1577X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 182057 control chromosomes (gnomAD). c.4729C>T has been reported in the literature in multiple individuals affected with Dystrophinopathies. Most of these individuals were affected with DMD (Duchenne Muscular Dystrophy)(e.g. Esterhuizen_2014, Flanigan_2011, Takeshima_2010) .These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Dilated cardiomyopathy 3B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Apr 06, 2023 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 22, 2020 | The p.R1577* pathogenic mutation (also known as c.4729C>T), located in coding exon 34 of the DMD gene, results from a C to T substitution at nucleotide position 4729. This changes the amino acid from an arginine to a stop codon within coding exon 34. This alteration has been reported in multiple individuals with Duchenne muscular dystrophy (DMD) (Takeshima Y et al. J. Hum. Genet., 2010 Jun;55:379-88; Sedlácková J et al. Neuromuscul. Disord., 2009 Nov;19:749-53; Yang J et al. BMC Med. Genet., 2013 Mar;14:29; Mah JK et al. Can J Neurol Sci, 2011 May;38:465-74; Suh MR et al. Yonsei Med. J., 2017 May;58:613-618; Vieitez I et al. Neurologia Mar;32:377-385; Kong X et al. BMC Med. Genet., 2019 08;20:139; Flanigan KM et al. Hum. Mutat., 2009 Dec;30:1657-66). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at