chrX-32207138-A-C

Variant names:

• chrX-32207138-A-C
• rs1456737
• NM_004006.3:c.6438+9778T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004006.3(DMD):​c.6438+9778T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 110,518 control chromosomes in the GnomAD database, including 8,676 homozygotes. There are 15,189 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.46 (8676 hom., 15189 hem., cov: 22)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.781
• Publications: 5 publications found

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]

DMD Gene-Disease associations (from GenCC):

• Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• dilated cardiomyopathy 3B

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• Duchenne and Becker muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• Duchenne muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• progressive muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.6438+9778T>G		intron_variant	Intron 44 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.6438+9778T>G		intron_variant	Intron 44 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.461 AC: 50977 AN: 110470 Hom.: 8678 Cov.: 22

Gnomad AFR AF: 0.334

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.479

Gnomad OTH AF: 0.478

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.462 AC: 51005 AN: 110518 Hom.: 8676 Cov.: 22 AF XY: 0.463 AC XY: 15189 AN XY: 32788

African (AFR) AF: 0.335 AC: 10203 AN: 30490

American (AMR) AF: 0.568 AC: 5884 AN: 10357

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1482 AN: 2623

East Asian (EAS) AF: 0.836 AC: 2922 AN: 3494

South Asian (SAS) AF: 0.577 AC: 1489 AN: 2579

European-Finnish (FIN) AF: 0.457 AC: 2680 AN: 5870

Middle Eastern (MID) AF: 0.593 AC: 128 AN: 216

European-Non Finnish (NFE) AF: 0.479 AC: 25233 AN: 52710

Other (OTH) AF: 0.483 AC: 729 AN: 1510

Alfa AF: 0.464 Hom.: 40728

Bravo AF: 0.471

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.49
DANN	Benign	0.59
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1456737; hg19: chrX-32225255;