X-32454660-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_004006.3(DMD):c.3603+2T>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., 0 hem., cov: 14)

Exomes 𝑓: 0.000012 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

DMD
NM_004006.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.30

Publications

1 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: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0154639175 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PP5

Variant X-32454660-A-T is Pathogenic according to our data. Variant chrX-32454660-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 94598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	Effect	Exon Rank	Protein	UniProt
DMD	NM_004006.3	MANE Select	c.3603+2T>A	splice_donor intron	N/A	NP_003997.2	P11532-1
DMD	NM_004009.3		c.3591+2T>A	splice_donor intron	N/A	NP_004000.1	P11532
DMD	NM_000109.4		c.3579+2T>A	splice_donor intron	N/A	NP_000100.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DMD	ENST00000357033.9	TSL:1 MANE Select	c.3603+2T>A	splice_donor intron	N/A	ENSP00000354923.3	P11532-1
DMD	ENST00000378677.6	TSL:5	c.3591+2T>A	splice_donor intron	N/A	ENSP00000367948.2	P11532-11
DMD	ENST00000420596.5	TSL:5	c.94-89461T>A	intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes

AF:

0.000229

AC:

AN:

56823

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000481

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000408

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000810

Gnomad FIN

AF:

0.000492

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000335

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000221

AC:

AN:

135786

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000471

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000122

AC:

AN:

820013

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

237563

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

22106

American (AMR)

AF:

0.0000417

AC:

AN:

23977

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15432

East Asian (EAS)

AF:

0.00

AC:

AN:

25180

South Asian (SAS)

AF:

0.00

AC:

AN:

36270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28410

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

2880

European-Non Finnish (NFE)

AF:

0.0000127

AC:

AN:

630269

Other (OTH)

AF:

0.00

AC:

AN:

35489

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.260

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000229

AC:

AN:

56851

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

14909

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000480

AC:

AN:

20824

American (AMR)

AF:

0.000407

AC:

AN:

4912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1353

East Asian (EAS)

AF:

0.00

AC:

AN:

1496

South Asian (SAS)

AF:

0.000815

AC:

AN:

1227

European-Finnish (FIN)

AF:

0.000492

AC:

AN:

2032

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000335

AC:

AN:

23847

Other (OTH)

AF:

0.00

AC:

AN:

742

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.240

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.000209

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Duchenne muscular dystrophy (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

1.0

PhyloP100

9.3

GERP RS

5.3

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.96

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.96

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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