rs72468638

chrX-32386455-T-C

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.4529A>G(p.Lys1510Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00271 in 1,199,881 control chromosomes in the GnomAD database, including 39 homozygotes. There are 1,089 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., 148 hem., cov: 22)
  • Exomes 𝑓: 0.0027 (36 hom. 941 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 8.02

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=0.016875923).
• BP6: Variant X-32386455-T-C is Benign according to our data. Variant chrX-32386455-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 94632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-32386455-T-C is described in Lovd as [Likely_benign]. Variant chrX-32386455-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00289 (321/111132) while in subpopulation EAS AF= 0.0127 (45/3543). AF 95% confidence interval is 0.00975. There are 3 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.4529A>G	p.Lys1510Arg	missense_variant	33/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.4529A>G	p.Lys1510Arg	missense_variant	33/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.00289 AC: 321 AN: 111083 Hom.: 3 Cov.: 22 AF XY: 0.00442 AC XY: 148 AN XY: 33503

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000762

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000912

Gnomad OTH AF: 0.00267

GnomAD3 exomes AF: 0.00567 AC: 1029 AN: 181352 Hom.: 13 AF XY: 0.00479 AC XY: 319 AN XY: 66564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.000269

Gnomad EAS exome AF: 0.0152

Gnomad SAS exome AF: 0.000473

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.00158

Gnomad OTH exome AF: 0.00582

GnomAD4 exome AF: 0.00270 AC: 2936 AN: 1088749 Hom.: 36 Cov.: 29 AF XY: 0.00265 AC XY: 941 AN XY: 355373

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000311

Gnomad4 EAS exome AF: 0.0243

Gnomad4 SAS exome AF: 0.000501

Gnomad4 FIN exome AF: 0.0426

Gnomad4 NFE exome AF: 0.000418

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00289 AC: 321 AN: 111132 Hom.: 3 Cov.: 22 AF XY: 0.00441 AC XY: 148 AN XY: 33562

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000762

Gnomad4 EAS AF: 0.0127

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.000912

Gnomad4 OTH AF: 0.00198

Alfa AF: 0.00160 Hom.: 64

Bravo AF: 0.000926

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.00509 AC: 617

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2020	Variant summary: DMD c.4529A>G (p.Lys1510Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0057 in 181352 control chromosomes in the gnomAD database (exomes dataset), including 13 homozygotes, and 319 hemizygotes. The observed variant frequency is approximately 500 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophinopathy phenotype (1.1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.4529A>G in individuals affected with Dystrophinopathies and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (3x) / likely benign (2x). Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

Duchenne muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 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.

Apr 20, 2017

- -

Dilated cardiomyopathy 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2016

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	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.;D;D
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-0.34	T
MutationTaster	Benign	0.00065	P;P
PrimateAI	Uncertain	0.66	T
Sift4G	Uncertain	0.030	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.44
MVP		0.76
MPC		0.084
ClinPred		0.036	T
GERP RS		5.5
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs72468638; hg19: chrX-32404572;