chrX-32448508-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004006.3(DMD):c.3734C>T(p.Thr1245Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0116 in 1,206,985 control chromosomes in the GnomAD database, including 169 homozygotes. There are 4,240 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. T1245T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0099 ( 14 hom., 315 hem., cov: 23)

Exomes 𝑓: 0.012 ( 155 hom. 3925 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 6.09

Publications

7 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023860931).

BP6

Variant X-32448508-G-A is Benign according to our data. Variant chrX-32448508-G-A is described in ClinVar as Benign. ClinVar VariationId is 94604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0798 is higher than 0.05.

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	UniProt
DMD	NM_004006.3	MANE Select	c.3734C>T	p.Thr1245Ile	missense	Exon 27 of 79	NP_003997.2	P11532-1
DMD	NM_004009.3		c.3722C>T	p.Thr1241Ile	missense	Exon 27 of 79	NP_004000.1	P11532
DMD	NM_000109.4		c.3710C>T	p.Thr1237Ile	missense	Exon 27 of 79	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DMD	ENST00000357033.9	TSL:1 MANE Select	c.3734C>T	p.Thr1245Ile	missense	Exon 27 of 79	ENSP00000354923.3	P11532-1
DMD	ENST00000378677.6	TSL:5	c.3722C>T	p.Thr1241Ile	missense	Exon 27 of 79	ENSP00000367948.2	P11532-11
DMD	ENST00000420596.5	TSL:5	c.94-83309C>T		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes

AF:

0.00995

AC:

1105

AN:

111014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00212

Gnomad AMI

AF:

0.00872

Gnomad AMR

AF:

0.0401

Gnomad ASJ

AF:

0.0103

Gnomad EAS

AF:

0.000285

Gnomad SAS

AF:

0.00184

Gnomad FIN

AF:

0.00295

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.0149

GnomAD2 exomes

AF:

0.0189

AC:

3452

AN:

182401

AF XY:

0.0144

show subpopulations

Gnomad AFR exome

AF:

0.00199

Gnomad AMR exome

AF:

0.0894

Gnomad ASJ exome

AF:

0.00820

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00438

Gnomad NFE exome

AF:

0.00919

Gnomad OTH exome

AF:

0.0127

GnomAD4 exome

AF:

0.0118

AC:

12882

AN:

1095919

Hom.:

155

Cov.:

AF XY:

0.0108

AC XY:

3925

AN XY:

362543

show subpopulations

African (AFR)

AF:

0.00153

AC:

AN:

26226

American (AMR)

AF:

0.0823

AC:

2894

AN:

35149

Ashkenazi Jewish (ASJ)

AF:

0.00877

AC:

169

AN:

19278

East Asian (EAS)

AF:

0.0000664

AC:

AN:

30135

South Asian (SAS)

AF:

0.00288

AC:

156

AN:

54083

European-Finnish (FIN)

AF:

0.00370

AC:

150

AN:

40493

Middle Eastern (MID)

AF:

0.00291

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.0107

AC:

9021

AN:

840495

Other (OTH)

AF:

0.00953

AC:

438

AN:

45943

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

457

914

1372

1829

2286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

390

780

1170

1560

1950

<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:

0.00995

AC:

1105

AN:

111066

Hom.:

Cov.:

AF XY:

0.00935

AC XY:

315

AN XY:

33694

show subpopulations

African (AFR)

AF:

0.00211

AC:

AN:

30757

American (AMR)

AF:

0.0400

AC:

417

AN:

10424

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

AN:

2617

East Asian (EAS)

AF:

0.000286

AC:

AN:

3500

South Asian (SAS)

AF:

0.00184

AC:

AN:

2713

European-Finnish (FIN)

AF:

0.00295

AC:

AN:

6103

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0104

AC:

544

AN:

52547

Other (OTH)

AF:

0.0147

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

146

183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0103

Hom.:

633

Bravo

AF:

0.0143

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.0109

AC:

ExAC

AF:

0.0139

AC:

1686

EpiCase

AF:

0.0104

EpiControl

AF:

0.00845

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

not provided (4)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 3B (1)

Duchenne muscular dystrophy (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.96

PhyloP100

6.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.7

REVEL

Benign

0.12

Sift

Benign

0.044

Sift4G

Uncertain

0.049

Polyphen

0.83

Vest4

0.31

MPC

0.019

ClinPred

0.036

GERP RS

3.1

gMVP

0.15

Mutation Taster

=94/6

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over