rs72468699

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004006.3(DMD):c.1337A>G(p.His446Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000217 in 1,202,965 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 99 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. H446H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 9 hem., cov: 21)

Exomes 𝑓: 0.00022 ( 0 hom. 90 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 6.66

Publications

3 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.055550426).

BP6

Variant X-32614448-T-C is Benign according to our data. Variant chrX-32614448-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94461.

BS2

High AC in GnomAd4 at 24 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.1337A>G	p.His446Arg	missense_variant	Exon 12 of 79	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.1337A>G	p.His446Arg	missense_variant	Exon 12 of 79	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes

AF:

0.000216

AC:

AN:

110892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000966

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00266

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000758

Gnomad OTH

AF:

0.00201

GnomAD2 exomes

AF:

0.000297

AC:

AN:

178462

AF XY:

0.000391

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000259

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.000228

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.000217

AC:

237

AN:

1092073

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

AN XY:

358887

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26180

American (AMR)

AF:

0.000200

AC:

AN:

34974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19253

East Asian (EAS)

AF:

0.00

AC:

AN:

30078

South Asian (SAS)

AF:

0.0000371

AC:

AN:

53838

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

40114

Middle Eastern (MID)

AF:

0.000487

AC:

AN:

4107

European-Non Finnish (NFE)

AF:

0.000170

AC:

142

AN:

837760

Other (OTH)

AF:

0.000262

AC:

AN:

45769

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000216

AC:

AN:

110892

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

AN XY:

33266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30557

American (AMR)

AF:

0.0000966

AC:

AN:

10357

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2626

East Asian (EAS)

AF:

0.00

AC:

AN:

3490

South Asian (SAS)

AF:

0.00

AC:

AN:

2650

European-Finnish (FIN)

AF:

0.00266

AC:

AN:

6019

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000758

AC:

AN:

52786

Other (OTH)

AF:

0.00201

AC:

AN:

1491

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.000133

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000297

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 3B

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Left ventricular noncompaction cardiomyopathy

Uncertain:1

Sep 29, 2014

Blueprint Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary dilated cardiomyopathy

Uncertain:1

Sep 29, 2014

Blueprint Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Jun 26, 2018

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

May 23, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19937601, 28416588) -

DMD-related disorder

Benign:1

Aug 30, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Duchenne muscular dystrophy

Benign:1

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 18, 2018

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

.;T;.;.;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.92

D;.;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.056

T;T;T;T;T

MetaSVM

Benign

-0.33

PhyloP100

6.7

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.9

.;D;.;D;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

.;D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;T

Polyphen

0.99, 1.0

.;D;.;.;D

Vest4

0.78

MVP

0.85

MPC

0.080

ClinPred

0.40

GERP RS

5.6

gMVP

0.82

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over