rs1800279

chrX-31478281-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_Moderate BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):c.8762A>G(p.His2921Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,209,039 control chromosomes in the GnomAD database, including 345 homozygotes. There are 11,312 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. H2921H) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.022 (24 hom., 722 hem., cov: 22)
  • Exomes 𝑓: 0.029 (321 hom. 10590 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:15
• Conservation: PhyloP100: 1.61

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 -18 ACMG points.

• PS1: Transcript NM_004006.3 (DMD) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• BP4: Computational evidence support a benign effect (MetaRNN=0.015792578).
• BP6: Variant X-31478281-T-C is Benign according to our data. Variant chrX-31478281-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 11269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31478281-T-C is described in Lovd as [Benign]. Variant chrX-31478281-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.022 (2442/110875) while in subpopulation NFE AF= 0.032 (1696/52924). AF 95% confidence interval is 0.0308. There are 24 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.8762A>G	p.His2921Arg	missense_variant	59/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.8762A>G	p.His2921Arg	missense_variant	59/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.0220 AC: 2443 AN: 110823 Hom.: 24 Cov.: 22 AF XY: 0.0218 AC XY: 721 AN XY: 33053

Gnomad AFR AF: 0.00371

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0260

Gnomad FIN AF: 0.0501

Gnomad MID AF: 0.0254

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0223

GnomAD3 exomes AF: 0.0256 AC: 4685 AN: 183282 Hom.: 39 AF XY: 0.0262 AC XY: 1773 AN XY: 67748

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0283

Gnomad FIN exome AF: 0.0419

Gnomad NFE exome AF: 0.0329

Gnomad OTH exome AF: 0.0325

GnomAD4 exome AF: 0.0289 AC: 31713 AN: 1098164 Hom.: 321 Cov.: 34 AF XY: 0.0291 AC XY: 10590 AN XY: 363528

Gnomad4 AFR exome AF: 0.00394

Gnomad4 AMR exome AF: 0.0156

Gnomad4 ASJ exome AF: 0.0213

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0317

Gnomad4 FIN exome AF: 0.0444

Gnomad4 NFE exome AF: 0.0305

Gnomad4 OTH exome AF: 0.0273

GnomAD4 genome AF: 0.0220 AC: 2442 AN: 110875 Hom.: 24 Cov.: 22 AF XY: 0.0218 AC XY: 722 AN XY: 33115

Gnomad4 AFR AF: 0.00370

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0261

Gnomad4 FIN AF: 0.0501

Gnomad4 NFE AF: 0.0320

Gnomad4 OTH AF: 0.0220

Alfa AF: 0.0306 Hom.: 1311

Bravo AF: 0.0193

TwinsUK AF: 0.0318 AC: 118

ALSPAC AF: 0.0322 AC: 93

ESP6500AA AF: 0.00444 AC: 17

ESP6500EA AF: 0.0297 AC: 200

ExAC AF: 0.0269 AC: 3270

EpiCase AF: 0.0336

EpiControl AF: 0.0315

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.His2921Arg in exon 59 of DMD: This variant is not expected to have clinical si gnificance because it has been identified in 3% (200/6728) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs1800279). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2019	Variant summary: DMD c.8762A>G (p.His2921Arg) results in a non-conservative amino acid change located in a spectrin repeat (IPR018159) of 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 0.026 in 200041 control chromosomes in the gnomAD database, including 42 homozygotes and 1923 hemizygotes. These data strongly suggest that the variant is benign. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (5x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 23, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Duchenne muscular dystrophy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Becker muscular dystrophy Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Sep 01, 1994

- -

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 28, 2017

- -

Dilated cardiomyopathy 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

DMD-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2015

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	0.063
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	9.5
Dann	Benign	0.70
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.67	T;.;.;.;.;T;.;T;T;.
MetaRNN	Benign	0.016	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.00034	A;A;A;A;A;A;A
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.75	N;.;N;N;N;.;N;.;N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;.;T;T;T;.;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;B;B;.;B;.;.;B
Vest4		0.073, 0.087, 0.089, 0.10, 0.099, 0.093, 0.069
MPC		0.037
ClinPred		0.0018	T
GERP RS		2.9
gMVP		0.23

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: rs1800279; hg19: chrX-31496398; COSMIC: COSV58889263; COSMIC: COSV58889263;