X-31147522-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_004006.3(DMD):c.10554-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000517 in 1,159,500 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000010 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.0000047 ( 0 hom. 0 hem. )

Consequence

DMD
NM_004006.3 splice_region, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.986

Publications

0 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:

ENSG00000297249 (HGNC:):

ENSG00000297249 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS2

High AC in GnomAdExome4 at 5 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.10554-4A>G	splice_region intron	N/A	NP_003997.2	P11532-1
DMD	NM_004009.3		c.10542-4A>G	splice_region intron	N/A	NP_004000.1	P11532
DMD	NM_000109.4		c.10530-4A>G	splice_region 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.10554-4A>G	splice_region intron	N/A	ENSP00000354923.3	P11532-1
DMD	ENST00000378723.7	TSL:1	c.1350-4A>G	splice_region intron	N/A	ENSP00000367997.3	P11532-6
DMD	ENST00000361471.8	TSL:1	c.1311-4A>G	splice_region intron	N/A	ENSP00000354464.4	P11532-5

Frequencies

GnomAD3 genomes

AF:

0.0000103

AC:

AN:

97004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000366

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000142

AC:

AN:

140524

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000910

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:

0.0000165

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000471

AC:

AN:

1062496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

332874

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25346

American (AMR)

AF:

0.00

AC:

AN:

32305

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18835

East Asian (EAS)

AF:

0.0000677

AC:

AN:

29542

South Asian (SAS)

AF:

0.00

AC:

AN:

49589

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39766

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4039

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

818305

Other (OTH)

AF:

0.00

AC:

AN:

44769

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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

AF:

0.0000103

AC:

AN:

97004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

21166

show subpopulations

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

African (AFR)

AF:

0.0000366

AC:

AN:

27357

American (AMR)

AF:

0.00

AC:

AN:

8431

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2349

East Asian (EAS)

AF:

0.00

AC:

AN:

3093

South Asian (SAS)

AF:

0.00

AC:

AN:

1763

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4015

Middle Eastern (MID)

AF:

0.00

AC:

AN:

207

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

47929

Other (OTH)

AF:

0.00

AC:

AN:

1236

⚠️ 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: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Duchenne muscular dystrophy (1)

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

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.82

PhyloP100

0.99

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.76

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.76

Position offset: -1

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over