Genetic Variant DMD:p.Glu440Lys (chrX-32644145-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004006.3(DMD):c.1318G>A(p.Glu440Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000163 in 1,205,363 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 59 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). Synonymous variant affecting the same amino acid position (i.e. E440E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00016 ( 0 hom. 52 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:8

Conservation

PhyloP100: 7.91

Publications

5 publications found

Variant links:

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

DMD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010299444).

BP6

Variant X-32644145-C-T is Benign according to our data. Variant chrX-32644145-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 161221.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000197 (22/111578) while in subpopulation EAS AF = 0.00566 (20/3532). AF 95% confidence interval is 0.00375. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 22 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMD	NM_004006.3	MANE Select	c.1318G>A	p.Glu440Lys	missense	Exon 11 of 79	NP_003997.2
DMD	NM_004009.3		c.1306G>A	p.Glu436Lys	missense	Exon 11 of 79	NP_004000.1
DMD	NM_000109.4		c.1294G>A	p.Glu432Lys	missense	Exon 11 of 79	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DMD	ENST00000357033.9	TSL:1 MANE Select	c.1318G>A	p.Glu440Lys	missense	Exon 11 of 79	ENSP00000354923.3
DMD	ENST00000288447.9	TSL:1	c.1294G>A	p.Glu432Lys	missense	Exon 11 of 18	ENSP00000288447.4
DMD	ENST00000447523.1	TSL:1	c.247-70299G>A		intron	N/A	ENSP00000395904.1

Frequencies

GnomAD3 genomes

AF:

0.000206

AC:

AN:

111526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000381

Gnomad EAS

AF:

0.00593

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000470

AC:

AN:

178649

AF XY:

0.000393

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000140

Gnomad EAS exome

AF:

0.00528

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000124

Gnomad OTH exome

AF:

0.000455

GnomAD4 exome

AF:

0.000160

AC:

175

AN:

1093785

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

359683

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26225

American (AMR)

AF:

0.00

AC:

AN:

34766

Ashkenazi Jewish (ASJ)

AF:

0.000312

AC:

AN:

19209

East Asian (EAS)

AF:

0.00425

AC:

128

AN:

30136

South Asian (SAS)

AF:

0.000619

AC:

AN:

53300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40322

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4115

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839775

Other (OTH)

AF:

0.000131

AC:

AN:

45937

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000197

AC:

AN:

111578

Hom.:

Cov.:

AF XY:

0.000207

AC XY:

AN XY:

33786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30785

American (AMR)

AF:

0.00

AC:

AN:

10462

Ashkenazi Jewish (ASJ)

AF:

0.000381

AC:

AN:

2624

East Asian (EAS)

AF:

0.00566

AC:

AN:

3532

South Asian (SAS)

AF:

0.00

AC:

AN:

2665

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6035

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53053

Other (OTH)

AF:

0.00

AC:

AN:

1520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000527

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Nov 21, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 28, 2019

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.1318G>A (p.Glu440Lys) results in a conservative amino acid change located in the Spectrin/alpha-actinin repeat 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 0.00043 in 195664 control chromosomes, predominantly at a frequency of 0.0053 within the East Asian subpopulation in the gnomAD database, including 24 hemizygotes. This frequency is significantly higher than expected for a pathogenic variant in DMD causing Dystrophinopathies, strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1318G>A has been reported in the literature in a family affected with Becker muscular dystrophy and it was found in cis with a pathogenic variant (DMD deletion of exons 45 to 53) in 3 affected males and 2 female carriers (Li_2012), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign and a submission derived from reference population cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

Becker muscular dystrophy

Uncertain:2

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:reference population

not provided

Benign:2

May 20, 2014

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is found in CARDIOMYOPATHY panel(s).

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DMD: BS2

Duchenne muscular dystrophy

Benign:2

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dystrophin deficiency

Uncertain:1

Apr 23, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jul 24, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.035

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.71

PhyloP100

7.9

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.29

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.0080

Polyphen

0.94

Vest4

0.62

MVP

0.84

MPC

0.028

ClinPred

0.11

GERP RS

5.8

gMVP

0.27

Mutation Taster

=36/64

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over