X-31120157-TTGAA-T

Variant summary

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

The NM_004006.3(DMD):c.*1758_*1761del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 111,277 control chromosomes in the GnomAD database, including 4 homozygotes. There are 129 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (4 hom., 128 hem., cov: 22)
  • Exomes 𝑓: 0.0033 (0 hom. 1 hem.)
• Consequence: DMD NM_004006.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

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 = 0.00512 (568/110975) while in subpopulation NFE AF= 0.00759 (400/52686). AF 95% confidence interval is 0.00698. There are 4 homozygotes in gnomad4. There are 128 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 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.*1758_*1761del		3_prime_UTR_variant	79/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.*1758_*1761del		3_prime_UTR_variant	79/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.00512 AC: 568 AN: 110922 Hom.: 4 Cov.: 22 AF XY: 0.00380 AC XY: 128 AN XY: 33690

Gnomad AFR AF: 0.00221

Gnomad AMI AF: 0.0631

Gnomad AMR AF: 0.00181

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00541

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00759

Gnomad OTH AF: 0.00466

GnomAD4 exome AF: 0.00331 AC: 1 AN: 302 Hom.: 0 AF XY: 0.00769 AC XY: 1 AN XY: 130

Gnomad4 FIN exome AF: 0.00336

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00512 AC: 568 AN: 110975 Hom.: 4 Cov.: 22 AF XY: 0.00379 AC XY: 128 AN XY: 33753

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.00181

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00541

Gnomad4 NFE AF: 0.00759

Gnomad4 OTH AF: 0.00460

Alfa AF: 0.00315 Hom.: 10

Bravo AF: 0.00478

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

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs751300992; hg19: chrX-31138274;