rs128626249

chrX-32342123-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004006.3(DMD):c.5899C>T(p.Arg1967Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000912 in 1,096,246 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. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1967R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 4.40

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 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-32342123-G-A is Pathogenic according to our data. Variant chrX-32342123-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32342123-G-A is described in Lovd as [Pathogenic]. Variant chrX-32342123-G-A is described in Lovd as [Likely_pathogenic]. Variant chrX-32342123-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.5899C>T	p.Arg1967Ter	stop_gained	41/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.5899C>T	p.Arg1967Ter	stop_gained	41/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000552 AC: 1 AN: 181045 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65875

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000535

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096246 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361852

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: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2017	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: 32559196, 31727011, 31919629, 30833962, 27363342, 19065519, 19937601, 19959795, 8401539, 18652600, 25525159, 15319032) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 19, 2017	- -

Duchenne muscular dystrophy Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Uncertain significance, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Nov 30, 2017	The observed variant c.5899C>T (p.Arg1967Ter) is not reported in 1000 Genomes and its minor allele frequency in ExAC databases is 0.00001328. The in silico prediction of the variant is disease causing by MutationTaster2. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change creates a premature translational stop signal (p.Arg1967*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Duchenne or Becker muscular dystrophy (PMID: 8401539, 18652600, 30833962). This variant is also known as c.6107C>T. ClinVar contains an entry for this variant (Variation ID: 11258). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2020

The p.R1967* pathogenic mutation (also known as c.5899C>T), located in coding exon 41 of the DMD gene, results from a C to T substitution at nucleotide position 5899. This changes the amino acid from an arginine to a stop codon within coding exon 41. This mutation has been detected in muscular dystrophy cohorts (Cunniff C et al. J Child Neurol, 2009 Apr;24:425-30; Takeshima Y et al. J Hum Genet, 2010 Jun;55:379-88; Park HJ et al. Clin Genet, 2017 03;91:403-410; Wang L et al. Front Genet, 2019 Feb;10:114; Okubo M et al. Hum Genet, 2020 Feb;139:247-255). In addition to the clinical data presented in the literature, 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	40
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
MutationTaster	Benign	1.0	A;A
Vest4		0.98
GERP RS		5.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs128626249; hg19: chrX-32360240; COSMIC: COSV63737423; COSMIC: COSV63737423;