rs140237546
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_004006.3(DMD):c.4072-245C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,123,334 control chromosomes in the GnomAD database, including 1 homozygotes. There are 71 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).
Frequency
Genomes: 𝑓 0.00048 ( 0 hom., 13 hem., cov: 22)
Exomes 𝑓: 0.00019 ( 1 hom. 58 hem. )
Consequence
DMD
NM_004006.3 intron
NM_004006.3 intron
Scores
2
Splicing: ADA: 0.00001554
2
Clinical Significance
Conservation
PhyloP100: 0.446
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
?
Variant X-32412158-G-A is Benign according to our data. Variant chrX-32412158-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 94610.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000476 (53/111271) while in subpopulation AMR AF= 0.00164 (17/10391). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd4 at 13 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DMD | NM_004006.3 | c.4072-245C>T | intron_variant | ENST00000357033.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DMD | ENST00000357033.9 | c.4072-245C>T | intron_variant | 1 | NM_004006.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000477 AC: 53AN: 111218Hom.: 0 Cov.: 22 AF XY: 0.000358 AC XY: 12AN XY: 33508
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GnomAD3 exomes AF: 0.000441 AC: 69AN: 156633Hom.: 1 AF XY: 0.000225 AC XY: 11AN XY: 48965
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GnomAD4 exome AF: 0.000192 AC: 194AN: 1012063Hom.: 1 Cov.: 30 AF XY: 0.000185 AC XY: 58AN XY: 313259
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GnomAD4 genome ? AF: 0.000476 AC: 53AN: 111271Hom.: 0 Cov.: 22 AF XY: 0.000387 AC XY: 13AN XY: 33571
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 05, 2015 | Variant classified as Uncertain Significance - Favor Benign. The c.48+4C>T varia nt in DMD has not been previously reported in individuals with cardiomyopathy, b ut has been identified in 0.2% (10/4843) of African chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140237546). T his variant is located in the 3' splice region. Although computational tools do not suggest an impact to splicing, this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the c.48+ 4C>T variant is uncertain, its frequency suggests that it is more likely to be b enign. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2019 | - - |
DMD-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 17, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at