rs151244052

chrX-31729720-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):c.7571G>A(p.Arg2524His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,209,257 control chromosomes in the GnomAD database, including 2 homozygotes. There are 55 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2524C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., 28 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 27 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.16

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009658515).
• BP6: Variant X-31729720-C-T is Benign according to our data. Variant chrX-31729720-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 161219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31729720-C-T is described in Lovd as [Likely_benign]. Variant chrX-31729720-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00102 (114/111689) while in subpopulation AFR AF= 0.00355 (109/30717). AF 95% confidence interval is 0.00301. There are 2 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.7571G>A	p.Arg2524His	missense_variant	52/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.7571G>A	p.Arg2524His	missense_variant	52/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 115 AN: 111637 Hom.: 2 Cov.: 23 AF XY: 0.000828 AC XY: 28 AN XY: 33817

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000316 AC: 58 AN: 183510 Hom.: 1 AF XY: 0.000177 AC XY: 12 AN XY: 67942

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 123 AN: 1097568 Hom.: 0 Cov.: 30 AF XY: 0.0000744 AC XY: 27 AN XY: 362942

Gnomad4 AFR exome AF: 0.00356

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.00102 AC: 114 AN: 111689 Hom.: 2 Cov.: 23 AF XY: 0.000826 AC XY: 28 AN XY: 33879

Gnomad4 AFR AF: 0.00355

Gnomad4 AMR AF: 0.0000951

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000163 Hom.: 9

Bravo AF: 0.00107

ESP6500AA AF: 0.00444 AC: 17

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000305 AC: 37

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2021	This variant is associated with the following publications: (PMID: 24055113, 21515508, 25637381) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2017	- -

Duchenne muscular dystrophy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

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

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 21, 2018

- -

Muscular dystrophy Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 16, 2021

- -

Primary dilated cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

-

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2018

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.82	T;.;.;.;T;.;T;T;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0097	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.090	N;N;N;N;.;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.96	T;T;T;T;.;T;.;T;T
Sift4G	Benign	0.69	T;T;T;T;T;T;T;T;T
Polyphen		0.0040, 1.0, 0.0060, 0.056	.;B;D;B;.;B;.;.;B
Vest4		0.33, 0.34, 0.31, 0.41, 0.32, 0.66, 0.32
MVP		0.88
MPC		0.071
ClinPred		0.025	T
GERP RS		4.4
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs151244052; hg19: chrX-31747837; COSMIC: COSV58903664;