chrX-32365029-A-T

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.5016T>A(p.Asn1672Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 1,208,793 control chromosomes in the GnomAD database, including 95 homozygotes. There are 1,291 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1672I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.020 ( 54 hom., 576 hem., cov: 22)

Exomes 𝑓: 0.0023 ( 41 hom. 715 hem. )

Consequence

DMD
NM_004006.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 0.179

Publications

6 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=0.0073643923).

BP6

Variant X-32365029-A-T is Benign according to our data. Variant chrX-32365029-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0635 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.5016T>A	p.Asn1672Lys	missense	Exon 35 of 79	NP_003997.2	P11532-1
DMD	NM_004009.3		c.5004T>A	p.Asn1668Lys	missense	Exon 35 of 79	NP_004000.1	P11532
DMD	NM_000109.4		c.4992T>A	p.Asn1664Lys	missense	Exon 35 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.5016T>A	p.Asn1672Lys	missense	Exon 35 of 79	ENSP00000354923.3	P11532-1
DMD	ENST00000378677.6	TSL:5	c.5004T>A	p.Asn1668Lys	missense	Exon 35 of 79	ENSP00000367948.2	P11532-11
DMD	ENST00000619831.5	TSL:5	c.984T>A	p.Asn328Lys	missense	Exon 7 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2165

AN:

110989

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00226

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00420

Gnomad NFE

AF:

0.000415

Gnomad OTH

AF:

0.0161

GnomAD2 exomes

AF:

0.00610

AC:

1117

AN:

183125

AF XY:

0.00446

show subpopulations

Gnomad AFR exome

AF:

0.0710

Gnomad AMR exome

AF:

0.00467

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00228

AC:

2506

AN:

1097753

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

715

AN XY:

363243

show subpopulations

African (AFR)

AF:

0.0683

AC:

1802

AN:

26379

American (AMR)

AF:

0.00546

AC:

192

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30163

South Asian (SAS)

AF:

0.00102

AC:

AN:

54139

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.00411

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.000233

AC:

196

AN:

841775

Other (OTH)

AF:

0.00530

AC:

244

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

187

281

374

468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.0196

AC:

2179

AN:

111040

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

576

AN XY:

33230

show subpopulations

African (AFR)

AF:

0.0659

AC:

2014

AN:

30556

American (AMR)

AF:

0.0109

AC:

113

AN:

10357

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3524

South Asian (SAS)

AF:

0.00189

AC:

AN:

2641

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5900

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000415

AC:

AN:

53014

Other (OTH)

AF:

0.0159

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

215

286

358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00325

Hom.:

Bravo

AF:

0.0225

ESP6500AA

AF:

0.0673

AC:

258

ESP6500EA

AF:

0.000743

AC:

ExAC

AF:

0.00685

AC:

831

EpiCase

AF:

0.000327

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (3)

Dilated cardiomyopathy 3B (2)

Cardiovascular phenotype (1)

Duchenne muscular dystrophy (1)

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

Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.82

MetaRNN

Benign

0.0074

MetaSVM

Benign

-1.0

PhyloP100

0.18

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.066

Sift

Uncertain

0.016

Sift4G

Benign

0.25

Polyphen

0.25

Vest4

0.22

MutPred

0.65

Gain of ubiquitination at N1672 (P = 0.017)

MVP

0.66

MPC

0.056

ClinPred

0.027

GERP RS

-0.67

gMVP

0.16

Mutation Taster

=90/10

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