X-31206567-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004006.3(DMD):c.9649+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (27532 hom., 27775 hem., cov: 23)
  • Exomes 𝑓: 0.87 (279734 hom. 299840 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.472

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-31206567-A-G is Benign according to our data. Variant chrX-31206567-A-G is described in ClinVar as [Benign]. Clinvar id is 94854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-31206567-A-G is described in Lovd as [Benign]. Variant chrX-31206567-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 27535 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.9649+15T>C		intron_variant		ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.9649+15T>C		intron_variant		1	NM_004006.3	P4

Frequencies

GnomAD3 genomes AF: 0.840 AC: 92965 AN: 110693 Hom.: 27535 Cov.: 23 AF XY: 0.842 AC XY: 27706 AN XY: 32893

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.908

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.803

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.888

Gnomad MID AF: 0.878

Gnomad NFE AF: 0.883

Gnomad OTH AF: 0.859

GnomAD3 exomes AF: 0.867 AC: 148595 AN: 171412 Hom.: 42875 AF XY: 0.870 AC XY: 49812 AN XY: 57240

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.922

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.802

Gnomad SAS exome AF: 0.835

Gnomad FIN exome AF: 0.883

Gnomad NFE exome AF: 0.884

Gnomad OTH exome AF: 0.887

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.874 AC: 938413 AN: 1073286 Hom.: 279734 Cov.: 23 AF XY: 0.874 AC XY: 299840 AN XY: 343168

Gnomad4 AFR exome AF: 0.730

Gnomad4 AMR exome AF: 0.921

Gnomad4 ASJ exome AF: 0.859

Gnomad4 EAS exome AF: 0.815

Gnomad4 SAS exome AF: 0.835

Gnomad4 FIN exome AF: 0.879

Gnomad4 NFE exome AF: 0.883

Gnomad4 OTH exome AF: 0.863

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.840 AC: 93027 AN: 110750 Hom.: 27532 Cov.: 23 AF XY: 0.843 AC XY: 27775 AN XY: 32960

Gnomad4 AFR AF: 0.734

Gnomad4 AMR AF: 0.908

Gnomad4 ASJ AF: 0.863

Gnomad4 EAS AF: 0.804

Gnomad4 SAS AF: 0.819

Gnomad4 FIN AF: 0.888

Gnomad4 NFE AF: 0.883

Gnomad4 OTH AF: 0.861

Alfa AF: 0.873 Hom.: 118090

Bravo AF: 0.839

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	c.9649+15T>C in intron 66 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 26.6% (1020/3830) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs2293668). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 12, 2018	Variant summary: DMD c.9649+15T>C 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 0.88 in 74144 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 79.032 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 benign. To our knowledge, no occurrence of c.9649+15T>C 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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Dilated cardiomyopathy 3B Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	- -

Duchenne muscular dystrophy Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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.

Aug 08, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	5.6
Dann	Benign	0.76

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: rs2293668; hg19: chrX-31224684; COSMIC: COSV58941457; COSMIC: COSV58941457;