rs2270672

Positions:

• chrX-31657979-G-A

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.8027+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 1,201,414 control chromosomes in the GnomAD database, including 50,207 homozygotes. There are 137,658 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (4449 hom., 10714 hem., cov: 22)
  • Exomes 𝑓: 0.35 (45758 hom. 126944 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.00

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=-0.7).
• BP6: Variant X-31657979-G-A is Benign according to our data. Variant chrX-31657979-G-A is described in ClinVar as [Benign]. Clinvar id is 94783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31657979-G-A is described in Lovd as [Benign]. Variant chrX-31657979-G-A is described in Lovd as [Pathogenic]. Variant chrX-31657979-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.41 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMD	NM_004006.3	c.8027+11C>T		intron_variant		ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.8027+11C>T		intron_variant		1	NM_004006.3	ENSP00000354923	P4

Frequencies

GnomAD3 genomes AF: 0.331 AC: 36514 AN: 110243 Hom.: 4449 Cov.: 22 AF XY: 0.329 AC XY: 10700 AN XY: 32547

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.302

Gnomad NFE AF: 0.352

Gnomad OTH AF: 0.297

GnomAD3 exomes AF: 0.332 AC: 60352 AN: 181665 Hom.: 6516 AF XY: 0.342 AC XY: 22773 AN XY: 66529

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.318

Gnomad EAS exome AF: 0.307

Gnomad SAS exome AF: 0.441

Gnomad FIN exome AF: 0.432

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.352 AC: 383534 AN: 1091114 Hom.: 45758 Cov.: 29 AF XY: 0.355 AC XY: 126944 AN XY: 357886

Gnomad4 AFR exome AF: 0.323

Gnomad4 AMR exome AF: 0.187

Gnomad4 ASJ exome AF: 0.313

Gnomad4 EAS exome AF: 0.289

Gnomad4 SAS exome AF: 0.435

Gnomad4 FIN exome AF: 0.431

Gnomad4 NFE exome AF: 0.354

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.331 AC: 36518 AN: 110300 Hom.: 4449 Cov.: 22 AF XY: 0.329 AC XY: 10714 AN XY: 32612

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.323

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.431

Gnomad4 FIN AF: 0.421

Gnomad4 NFE AF: 0.352

Gnomad4 OTH AF: 0.293

Alfa AF: 0.347 Hom.: 21278

Bravo AF: 0.317

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 01, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.8027+11C>T in intron 54 of DMD: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 35.1% (2361/6725) of European American chromoso mes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs .washington.edu/EVS; dbSNP rs2270672). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2018	Variant summary: DMD c.8027+11C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 0.34 in 198201 control chromosomes in the gnomAD database, including 7231 homozygotes and 25267 hemizygotes. The observed variant frequency is approximately 30-fold above the estimated maximal expected allele frequency for a pathogenic variant in DMD causing Dystrophiopathies phenotype (0.011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.8027+11C>T 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 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Dilated cardiomyopathy 3B Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Duchenne muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	10
DANN	Benign	0.68

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: rs2270672; hg19: chrX-31676096;