rs113726961

chrX-33211320-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004006.3(DMD):c.-8T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00449 in 1,206,900 control chromosomes in the GnomAD database, including 158 homozygotes. There are 1,442 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (74 hom., 634 hem., cov: 22)
  • Exomes 𝑓: 0.0027 (84 hom. 808 hem.)
• Consequence: DMD NM_004006.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.42

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-33211320-A-T is Benign according to our data. Variant chrX-33211320-A-T is described in ClinVar as [Benign]. Clinvar id is 94419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-33211320-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.-8T>A		5_prime_UTR_variant	1/79	ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.-8T>A		5_prime_UTR_variant	1/79	1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 2511 AN: 111333 Hom.: 74 Cov.: 22 AF XY: 0.0187 AC XY: 626 AN XY: 33545

Gnomad AFR AF: 0.0772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00973

Gnomad ASJ AF: 0.00340

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00422

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.0193

GnomAD3 exomes AF: 0.00664 AC: 1179 AN: 177614 Hom.: 29 AF XY: 0.00428 AC XY: 269 AN XY: 62790

Gnomad AFR exome AF: 0.0782

Gnomad AMR exome AF: 0.00355

Gnomad ASJ exome AF: 0.00405

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000383

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000205

Gnomad OTH exome AF: 0.00385

GnomAD4 exome AF: 0.00265 AC: 2905 AN: 1095516 Hom.: 84 Cov.: 30 AF XY: 0.00224 AC XY: 808 AN XY: 361368

Gnomad4 AFR exome AF: 0.0822

Gnomad4 AMR exome AF: 0.00429

Gnomad4 ASJ exome AF: 0.00466

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000159

Gnomad4 OTH exome AF: 0.00729

GnomAD4 genome AF: 0.0226 AC: 2517 AN: 111384 Hom.: 74 Cov.: 22 AF XY: 0.0189 AC XY: 634 AN XY: 33606

Gnomad4 AFR AF: 0.0773

Gnomad4 AMR AF: 0.00962

Gnomad4 ASJ AF: 0.00340

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00149

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000188

Gnomad4 OTH AF: 0.0191

Alfa AF: 0.0127 Hom.: 68

Bravo AF: 0.0260

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2018	Variant summary: DMD c.-8T>A is located in the untranslated mRNA region upstream of the initiation codon. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.01 in 68568 control chromosomes, predominantly at a frequency of 0.081 within the African or African-American subpopulation in the ExAC database, including 22 homozygotes. The observed variant frequency within African or African-American control individuals in the ExAC database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophiopathies phenotype (0.011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.-8T>A in individuals affected with Dystrophiopathies and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.-8T>A in exon 1 of DMD: This variant is not expected to have clinical signific ance because it has been identified in 7.8% (299/3833) of African American chrom osomes from a broad population by the NHLBI Exome Sequencing Project (http://evs .gs.washington.ed -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 09, 2017

- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Aug 15, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	9.5
Dann	Benign	0.71

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: rs113726961; hg19: chrX-33229437;