NM_004006.3:c.837G>A

Variant names:

• chrX-32697993-C-T
• rs1800265
• NM_004006.3:c.837G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004006.3(DMD):​c.837G>A​(p.Thr279Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0285 in 1,189,000 control chromosomes in the GnomAD database, including 5,191 homozygotes. There are 8,756 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T279T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (2603 hom., 3679 hem., cov: 21)
  • Exomes 𝑓: 0.017 (2588 hom. 5077 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.189
• Publications: 8 publications found

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]

DMD Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant X-32697993-C-T is Benign according to our data. Variant chrX-32697993-C-T is described in ClinVar as Benign. ClinVar VariationId is 94805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.189 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.837G>A	p.Thr279Thr	synonymous_variant	Exon 9 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.837G>A	p.Thr279Thr	synonymous_variant	Exon 9 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.138 AC: 14972 AN: 108487 Hom.: 2600 Cov.: 21

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0885

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0215

Gnomad NFE AF: 0.00177

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.0490 AC: 7399 AN: 150946 AF XY: 0.0328

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.0685

Gnomad ASJ exome AF: 0.00230

Gnomad EAS exome AF: 0.00684

Gnomad FIN exome AF: 0.0000729

Gnomad NFE exome AF: 0.00168

Gnomad OTH exome AF: 0.0316

GnomAD4 exome AF: 0.0174 AC: 18842 AN: 1080469 Hom.: 2588 Cov.: 30 AF XY: 0.0145 AC XY: 5077 AN XY: 351101

African (AFR) AF: 0.491 AC: 12803 AN: 26076

American (AMR) AF: 0.0713 AC: 2312 AN: 32429

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 34 AN: 19038

East Asian (EAS) AF: 0.00955 AC: 281 AN: 29426

South Asian (SAS) AF: 0.00983 AC: 509 AN: 51797

European-Finnish (FIN) AF: 0.000406 AC: 16 AN: 39454

Middle Eastern (MID) AF: 0.0229 AC: 94 AN: 4100

European-Non Finnish (NFE) AF: 0.00116 AC: 966 AN: 832723

Other (OTH) AF: 0.0402 AC: 1827 AN: 45426

GnomAD4 genome AF: 0.138 AC: 15013 AN: 108531 Hom.: 2603 Cov.: 21 AF XY: 0.119 AC XY: 3679 AN XY: 31021

African (AFR) AF: 0.471 AC: 13808 AN: 29313

American (AMR) AF: 0.0882 AC: 889 AN: 10075

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2624

East Asian (EAS) AF: 0.00696 AC: 24 AN: 3450

South Asian (SAS) AF: 0.0105 AC: 26 AN: 2482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5753

Middle Eastern (MID) AF: 0.0236 AC: 5 AN: 212

European-Non Finnish (NFE) AF: 0.00177 AC: 93 AN: 52468

Other (OTH) AF: 0.112 AC: 165 AN: 1477

Alfa AF: 0.0458 Hom.: 503

Bravo AF: 0.167

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jan 13, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr279Thr in exon 09 of DMD: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 48% (1838/3833) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs1800265). -

Jul 19, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DMD c.837G>A results in a synonymous change. The variant allele was found at a frequency of 0.087 in 40353 control chromosomes, predominantly at a frequency of 0.52 within the African or African-American subpopulation in the ExAC database, including 620 homozygotes. The observed variant frequency within African or African-American control individuals in the ExAC database is approximately 46.51 fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophiopathies phenotype (0.011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.837G>A in individuals affected with Dystrophiopathies and no experimental evidence demonstrating its impact on protein function have been reported. Six 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/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Jan 17, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 11, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 20, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 3B Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Duchenne muscular dystrophy Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 26, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.34
CADD	Benign	0.78
DANN	Benign	0.72
PhyloP100		0.19
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1800265; hg19: chrX-32716110; COSMIC: COSV55860277;