rs886042106

Variant names:

• chrX-33174335-C-T
• rs886042106
• NM_004006.3:c.31+36947G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_004006.3(DMD):​c.31+36947G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 0.0790

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-33174335-C-T is Pathogenic according to our data. Variant chrX-33174335-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 281179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-33174335-C-T is described in Lovd as [Pathogenic]. Variant chrX-33174335-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.31+36947G>A		intron_variant	Intron 1 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.31+36947G>A		intron_variant	Intron 1 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Mar 22, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies including Western blot analysis demonstrate that this defect results in greatly reduced expression of wild type protein and RNA studies show that the variant introduces a leaky splice acceptor site that results in the retention of a cryptic exon, that creates a frameshift which is predicted to result in a null allele (PMID: 17041906, 14659407); No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 36048237, 33050418, 19823873, 30907348, 14659407, 33101180, 17041906, 33159473) -

Mar 21, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Becker muscular dystrophy Pathogenic:2

Sep 01, 2024

Solve-RD Consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The variant is a deep intronic substitution in DMD, identified in a male patient with suspected titinopathy, presenting with progressive proximal muscle weakness and myopathic features in his muscle biopsy. The variant has previously been shown to cause Becker muscular dystrophy through the exonization of a 149 bp sequence within intron 1 of DMD (PMID: 31919629). This variant was confirmed by the submitting clinician to impact a gene that corresponds with the phenotype of the affected individual, and thus deemed to be causative for their condition. -

Mar 04, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency Pathogenic:1

Jan 25, 2021

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Pathogenic:1

Dec 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 1 of the DMD gene. It does not directly change the encoded amino acid sequence of the DMD protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individual(s) with Becker muscular dystrophy (PMID: 14659407, 17041906). This variant is also known as IVS1+36947G>A and IVS1M-154188G>A. ClinVar contains an entry for this variant (Variation ID: 281179). Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 14659407, 17041906). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Dec 04, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31+36947G>A intronic variant results from a G to A substitution 36947 nucleotides after coding exon 1 in the DMD gene. This nucleotide position is not well conserved in available vertebrate species. This alteration has been detected in two unrelated patients with Becker muscular dystrophy (BMD) (Béroud C et al. Neuromuscul. Disord., 2004 Jan;14:10-8; Deburgrave N et al. Hum. Mutat., 2007 Feb;28:183-95). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Using the BDGP and ESEfinder in silico splicing prediction tools, this alteration is predicted to create a new alternate splice acceptor site. RNA studies indicate that this alteration results in the activation of a cryptic exon, resulting in the incorporation of 149 intronic nucleotides between exons 1 and 2, a frameshift, and a predicted alternate stop codon (Béroud C et al. Neuromuscul. Disord., 2004 Jan;14:10-8). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Pathogenic	26
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.94		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886042106; hg19: chrX-33192452;