X-32461403-T-C

Position:

• chrX-32461403-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_004006.3(DMD):​c.3432+2036A>G 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:6
• Conservation: PhyloP100: -0.384

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 11 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-32461403-T-C is Pathogenic according to our data. Variant chrX-32461403-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 455893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32461403-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.3432+2036A>G		intron_variant		ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.3432+2036A>G		intron_variant		1	NM_004006.3	P4

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Duchenne muscular dystrophy Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jun 03, 2020	The hemizygous c.3432+2036A>G variant in DMD was identified by our study in 1 individual with muscular dystrophy. The variant has been reported in 3 individuals of with Becker muscular dystrophy (PMID: 12754707; LOVD, PMID: 16770791), and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID: 455893) as likely pathogenic by Invitae. In vitro functional studies provide some evidence that the c.3432+2036A>G variant may impact protein function (PMID: 12754707). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for Becker muscular dystrophy. ACMG/AMP Criteria applied: PM2, PP3, PS3_supporting, PS4_moderate (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 05, 2022	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. For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in inclusion of a pseudoexon and introduces a premature termination codon (PMID: 12754707). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 455893). This variant is also known as IVS25+2036A>G. This variant has been observed in individuals with features of Becker muscular dystrophy (PMID: 12754707, 16770791). This sequence change falls in intron 25 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. -

Becker muscular dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2024

No data available from control populations to assess the frequency of this variant; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 28597072, 31443951, 12754707, 19823873, 16770791, 33050418) -

DMD-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 24, 2024

The DMD c.3432+2036A>G variant is predicted to interfere with splicing. This variant was reported in the hemizygous state in a male patient with subclinical Becker muscular dystrophy (Tuffery-Giraud et al. 2003. PubMed ID: 12754707). mRNA studies in patient's muscle tissue showed that this variant results in the activation of an intronic pseudoexon leading to a frameshift and premature termination codon. Of note, a mixture of normal spliced transcript was also found in the patient's muscle tissues, suggested by the authors explaining a milder phenotype (Tuffery-Giraud et al. 2003. PubMed ID: 12754707). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 10, 2020

The c.3432+2036A>G intronic variant results from an A to G substitution 2036 nucleotides after coding exon 25 in the DMD gene. This variant was reported in a Becker muscular dystrophy case with milder phenotype, including elevated serum CK level, proximal muscle weakness, and calf enlargement; RNA studies showed a mix of normal and abnormally spliced transcripts which incorporated an out-of-frame pseudoexon within the intron (Tuffery-Giraud S et al. Hum. Mutat., 2003 Jun;21:608-14). This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create new alternate splice acceptor and donor sites; however, direct evidence is unavailable. 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	-0.90
CADD	Uncertain	23
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.72		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.72		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs182575709; hg19: chrX-32479520;