X-31120472-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004006.3(DMD):c.*1447A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 110,946 control chromosomes in the GnomAD database, including 5,687 homozygotes. There are 10,870 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (5687 hom., 10870 hem., cov: 23)
  • Exomes 𝑓: 0.11 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-31120472-T-C is Benign according to our data. Variant chrX-31120472-T-C is described in ClinVar as [Benign]. Clinvar id is 368213.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-31120472-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.*1447A>G		3_prime_UTR_variant	79/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.*1447A>G		3_prime_UTR_variant	79/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.338 AC: 37518 AN: 110883 Hom.: 5681 Cov.: 23 AF XY: 0.326 AC XY: 10823 AN XY: 33181

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.248

Gnomad ASJ AF: 0.180

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.238

Gnomad MID AF: 0.254

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.312

GnomAD4 exome AF: 0.111 AC: 1 AN: 9 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3

Gnomad4 FIN exome AF: 0.00

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.339 AC: 37573 AN: 110937 Hom.: 5687 Cov.: 23 AF XY: 0.327 AC XY: 10870 AN XY: 33245

Gnomad4 AFR AF: 0.601

Gnomad4 AMR AF: 0.247

Gnomad4 ASJ AF: 0.180

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.224

Gnomad4 FIN AF: 0.238

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.318

Alfa AF: 0.244 Hom.: 13100

Bravo AF: 0.355

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated cardiomyopathy 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	5.6
Dann	Benign	0.74

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: rs3361; hg19: chrX-31138589;