X-31119681-A-AACTT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004006.3(DMD):c.*2237_*2238insAAGT 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.*2237_*2238insAAGT		3_prime_UTR_variant	79/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.*2237_*2238insAAGT		3_prime_UTR_variant	79/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 1590 AN: 111869 Hom.: 14 Cov.: 22 AF XY: 0.0119 AC XY: 407 AN XY: 34097

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: 4 AN: 296 Hom.: 0 Cov.: 0 AF XY: 0.0161 AC XY: 2 AN XY: 124

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0142 AC: 1589 AN: 111918 Hom.: 14 Cov.: 22 AF XY: 0.0119 AC XY: 408 AN XY: 34156

Gnomad4 AFR AF: 0.00395

Gnomad4 AMR AF: 0.0147

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.0109

Gnomad4 SAS AF: 0.00367

Gnomad4 FIN AF: 0.0161

Gnomad4 NFE AF: 0.0215

Gnomad4 OTH AF: 0.0111

Bravo AF: 0.0148

Asia WGS AF: 0.00519 AC: 13 AN: 2516

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 3B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs202154420; hg19: chrX-31137798;