rs771877780

chrX-31729736-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004006.3(DMD):c.7555G>A(p.Asp2519Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000058 in 1,207,821 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3 B:1
• Conservation: PhyloP100: 6.67

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27373123).
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.7555G>A	p.Asp2519Asn	missense_variant	52/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.7555G>A	p.Asp2519Asn	missense_variant	52/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111885 Hom.: 0 Cov.: 23 AF XY: 0.0000587 AC XY: 2 AN XY: 34065

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000559

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000272 AC: 5 AN: 183507 Hom.: 0 AF XY: 0.0000442 AC XY: 3 AN XY: 67943

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000361

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1095936 Hom.: 0 Cov.: 29 AF XY: 0.00000830 AC XY: 3 AN XY: 361320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111885 Hom.: 0 Cov.: 23 AF XY: 0.0000587 AC XY: 2 AN XY: 34065

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000559

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2015	The D2519N missense variant has been reported previously as de novo in a male with elevated CK level, calf hypertrophy, and a clinical diagnosis of Duchenne muscular dystrophy (Wang et al., 2014). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D2519N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. Therefore, D2519N is interpreted as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 04, 2022	The DMD c.7555G>A; p.Asp2519Asn variant (rs771877780) is reported in the literature as occurring de novo in a male diagnosed with muscular dystrophy and in a female with an increased CK undergoing carrier screening (Han 2020, Wang 2014). This variant is reported in the ClinVar database with conflicting classifications (Variation ID: 427170). This variant is found in the East Asian population with an allele frequency of 0.04% (6/14,879 alleles, including 4 hemizygotes) in the Genome Aggregation Database. The aspartic acid at codon 2519 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.254). Although the number of hemizygotes in the Genome Aggregation Database indicates this variant may be a rare benign variant, due to conflicting information, the clinical significance of the p.Asp2519Asn variant is uncertain at this time. References: Han S et al. Population-Wide Duchenne Muscular Dystrophy Carrier Detection by CK and Molecular Testing. Biomed Res Int. 2020 Sep 27;2020:8396429. PMID: 33029525. Wang Y et al. Whole dystrophin gene analysis by next-generation sequencing: a comprehensive genetic diagnosis of Duchenne and Becker muscular dystrophy. Mol Genet Genomics. 2014 Oct;289(5):1013-21. PMID: 24770780. -

Duchenne muscular dystrophy Pathogenic:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Obstetrics, Zhejiang Provincial People's Hospital, Zhejiang Provincial People's Hospital	Aug 16, 2020	The D2519N missense variant was not observed in 1000 Genome database, ESP 6500 and genomAD. It was a presumed de novo variant in a female with elevated CK and harboring non-DMD family history. This substitution occurs at a position that is conserved across species (SIFT and PolyPhen predicted it deleterious and probably damaging). Therefore, D2519N is interpreted as a likely pathogenic variant. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 19, 2023

Variant summary: DMD c.7555G>A (p.Asp2519Asn) results in a conservative amino acid change located in the central rod domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.9e-05 in 205897 control chromosomes, predominantly at a frequency of 0.0004 within the East Asian subpopulation in the gnomAD database, including 4 hemizygotes. The available data on variant occurrences in the general population suggest the variant could be a benign polymorphism found predominantly in individuals of East Asian ancestry, but are ultimately insufficient to allow any conclusion about variant significance. c.7555G>A has been reported in the literature as de novo in a male child affected with Duchenne Muscular Dystrophy (DMD) (Wang_2013) as well as in a female carrier with slightly elevated creatine kinase levels but no family history of DMD (Han_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33029525, 24770780). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Three submitters classified the variant as pathogenic/likely pathogenic, two classified it as uncertain significance, and one submitter classified it as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2022

The p.D2519N variant (also known as c.7555G>A), located in coding exon 52 of the DMD gene, results from a G to A substitution at nucleotide position 7555. The aspartic acid at codon 2519 is replaced by asparagine, an amino acid with highly similar properties. This variant was described as de novo in one male reported to have symptoms of Duchenne muscular dystrophy (DMD), although clinical details were limited (Wang Y et al. Mol Genet Genomics, 2014 Oct;289:1013-21). This variant was also detected in a female with elevated creatine kinase (CK) levels who had no skeletal muscular or cardiac findings, and known family history of DMD (Han S et al. Biomed Res Int, 2020 Sep;2020:8396429). Based on data from gnomAD, the A allele has an overall frequency of 0.0029%( 6/205497) total alleles studied, with 4 hemizygotes observed. The highest observed frequency was 0.0403% (6/14879) of East Asian alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.47
Cadd	Uncertain	23
Dann	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;.;.;.;D;.;D;D;.
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.35	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	D;D;D;D;.;D;.;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D;D;D;D;.;D;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.99	.;D;D;D;.;D;.;.;D
Vest4		0.57, 0.52, 0.52, 0.69, 0.61, 0.53, 0.80, 0.42
MutPred		0.46		.;.;.;.;.;.;.;Loss of ubiquitination at K2514 (P = 0.0705);.;
MVP		0.71
MPC		0.070
ClinPred		0.69	D
GERP RS		5.2
gMVP		0.52

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: rs771877780; hg19: chrX-31747853; COSMIC: COSV58901806;