Genetic Variant DMD:c.*2234_*2237dupAAGT (chrX-31119681-A-AACTT) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_004006.3(DMD):c.*2234_*2237dupAAGT variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0142 in 112,214 control chromosomes in the GnomAD database, including 14 homozygotes. There are 410 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.014 ( 14 hom., 408 hem., cov: 22)

Exomes 𝑓: 0.014 ( 0 hom. 2 hem. )

Consequence

DMD
NM_004006.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.26

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 links:

ENSG00000297249 (HGNC:):

ENSG00000297249 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (1589/111918) while in subpopulation NFE AF = 0.0215 (1140/53086). AF 95% confidence interval is 0.0204. There are 14 homozygotes in GnomAd4. There are 408 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 1589 XLR,XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3 link	c.2234_2237dupAAGT		3_prime_UTR_variant	Exon 79 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.2234_2237dupAAGT		3_prime_UTR_variant	Exon 79 of 79	1	NM_004006.3	ENSP00000354923.3		A0A075B6G3

Frequencies

GnomAD3 genomes

AF:

0.0142

AC:

1590

AN:

111869

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00396

Gnomad AMI

AF:

0.00587

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.00113

Gnomad EAS

AF:

0.0111

Gnomad SAS

AF:

0.00366

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.0167

Gnomad NFE

AF:

0.0215

Gnomad OTH

AF:

0.0113

GnomAD4 exome

AF:

0.0135

AC:

AN:

296

Hom.:

Cov.:

AF XY:

0.0161

AC XY:

AN XY:

124

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.0137

AC:

AN:

292

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0142

AC:

1589

AN:

111918

Hom.:

Cov.:

AF XY:

0.0119

AC XY:

408

AN XY:

34156

show subpopulations

African (AFR)

AF:

0.00395

AC:

122

AN:

30907

American (AMR)

AF:

0.0147

AC:

154

AN:

10499

Ashkenazi Jewish (ASJ)

AF:

0.00113

AC:

AN:

2648

East Asian (EAS)

AF:

0.0109

AC:

AN:

3591

South Asian (SAS)

AF:

0.00367

AC:

AN:

2724

European-Finnish (FIN)

AF:

0.0161

AC:

AN:

6035

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0215

AC:

1140

AN:

53086

Other (OTH)

AF:

0.0111

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

121

182

242

303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00446

Hom.:

Bravo

AF:

0.0148

Asia WGS

AF:

0.00519

AC:

AN:

2516

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 3B

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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chrX-31119681-A-AACTT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over