rs147927593

Variant names:

Variant summary

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

The NM_004006.3(DMD):c.5984A>T(p.Tyr1995Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000183 in 1,207,753 control chromosomes in the GnomAD database, including 2 homozygotes. There are 58 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1995D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., 33 hem., cov: 23)

Exomes 𝑓: 0.000089 ( 1 hom. 25 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 4.12

Publications

2 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=0.009187996).

BP6

Variant X-32310215-T-A is Benign according to our data. Variant chrX-32310215-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94687.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0011 (123/111698) while in subpopulation AFR AF = 0.00379 (117/30877). AF 95% confidence interval is 0.00323. There are 1 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 123 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.5984A>T	p.Tyr1995Phe	missense_variant	Exon 42 of 79	ENST00000357033.9	NP_003997.2	P11532

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9 link	c.5984A>T	p.Tyr1995Phe	missense_variant	Exon 42 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

122

AN:

111644

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00377

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000365

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00201

GnomAD2 exomes

AF:

0.000231

AC:

AN:

182164

AF XY:

0.000223

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000894

AC:

AN:

1096055

Hom.:

Cov.:

AF XY:

0.0000690

AC XY:

AN XY:

362349

show subpopulations

African (AFR)

AF:

0.00293

AC:

AN:

26284

American (AMR)

AF:

0.000200

AC:

AN:

35062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19304

East Asian (EAS)

AF:

0.00

AC:

AN:

30127

South Asian (SAS)

AF:

0.00

AC:

AN:

54082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40486

Middle Eastern (MID)

AF:

0.000485

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

840621

Other (OTH)

AF:

0.000218

AC:

AN:

45964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.00110

AC:

123

AN:

111698

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

AN XY:

34084

show subpopulations

African (AFR)

AF:

0.00379

AC:

117

AN:

30877

American (AMR)

AF:

0.00

AC:

AN:

10521

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3510

South Asian (SAS)

AF:

0.000366

AC:

AN:

2732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6145

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52853

Other (OTH)

AF:

0.00198

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.000214

Hom.:

Bravo

AF:

0.000941

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000272

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B

Uncertain:1Benign:1

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DMD NM_004006.2 exon 42 p.Tyr1995Phe (c.5984A>T): This variant has not been reported in the literature but is present in 0.3% (64/18143) of African alleles, including 22 hemizygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/X-32328332-T-A). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:94687). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Sep 08, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Apr 14, 2025

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP1;BP4;BP6 -

not provided

Benign:2

May 25, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2018

Athena Diagnostics

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

Oct 17, 2017

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Duchenne muscular dystrophy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 09, 2017

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

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.24

.;T;.;.

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.74

T;.;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.0092

T;T;T;T

MetaSVM

Benign

-0.95

PhyloP100

4.1

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.39

.;N;.;N

REVEL

Benign

0.099

Sift

Benign

0.69

.;T;.;T

Sift4G

Benign

0.66

T;T;T;T

Polyphen

0.60

.;P;.;.

Vest4

0.32

MVP

0.79

MPC

0.027

ClinPred

0.057

GERP RS

4.9

gMVP

0.070

Mutation Taster

=100/0

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