rs398123923

chrX-33211281-C-AchrX-33211281-C-GchrX-33211281-C-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PM2 PP3_Strong PP5_Very_Strong

The NM_004006.3(DMD):c.31+1G>T variant causes a splice donor change. The variant allele was found at a frequency of 0.000000913 in 1,095,773 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.75

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 22 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-33211281-C-A is Pathogenic according to our data. Variant chrX-33211281-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 94554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-33211281-C-A is described in Lovd as [Likely_pathogenic]. Variant chrX-33211281-C-A is described in Lovd as [Pathogenic]. Variant chrX-33211281-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.31+1G>T		splice_donor_variant		ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.31+1G>T		splice_donor_variant		1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095773 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361653

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 3B Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Dec 16, 2022	PVS1, PM2, PP5 -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Aug 18, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	KTest Genetics, KTest	-	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2014	c.31+1 G>T: IVS1+1 G>T in intron 1 of the DMD gene (NM_004006.2). The c.31+1 G>T mutation in the DMD gene has been reported numerous times in association with DCM and/or Becker Muscular dystrophy (Milasin J et al., 1996; Aartsma-Rus et al., 2006; http://www.dmd.nl/nmdb/home.php). Furthermore, the c.31+1 G>T mutation was not observed inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This mutation destroys the canonical splice donor site in intron 1 and is predicted to cause abnormal gene splicing. The mutation is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Numerous other splice site mutations in the DMD gene have been reported in association with cardiomyopathy or dystrophinopathy. In summary, c.31+1 G>T in the DMD gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 31, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2018	- -

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

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 16, 2017

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2019

The c.31+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 1 of the DMD gene. This mutation, also referred to as IVS1+1G>T, has been detected in several individuals presenting with early onset X-linked dilated cardiomyopathy (DCM), often requiring heart transplant, and has also been reported to segregated with DCM in families (Milasin J et al. Hum. Mol. Genet., 1996 Jan;5:73-9; Feng J et al. J. Am. Coll. Cardiol., 2002 Sep;40:1120-4; Neri M et al. Neuromuscul. Disord., 2007 Dec;17:913-8). This mutation has also been detected in dystrophinopathy and Becker Muscular Dystrophy cohorts; however clinical detail was limited (Cho A et al. Muscle Nerve, 2017 05;55:727-734; Okubo M et al. Orphanet J Rare Dis, 2017 08;12:149; Deburgrave N et al. Hum. Mutat., 2007 Feb;28:183-95). Trancscriptional studies from patients with this mutation indicated absence of transcript from the muscle promotor in skeletal and heart muscle, while upregulation of alternate promoters appeared to result in production of other DMD isoforms in skeletal muscle, albeit at reduced levels (Milasin J et al. Hum. Mol. Genet., 1996 Jan;5:73-9; Neri M et al. Neuromuscul. Disord., 2007 Dec;17:913-8). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Duchenne muscular dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 06, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the DMD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DMD are known to be pathogenic (PMID: 16770791, 25007885). Disruption of this splice site has been observed in individuals with dilated cardiomyopathy and/or DMD-related muscular dystrophy (PMID: 8789442, 12354438, 17041906, 27593222). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 94554). This variant is also known as IVS1+1G>T. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	32
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	D;D
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		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: rs398123923; hg19: chrX-33229398;