chrX-32269126-T-C

Variant names:

• chrX-32269126-T-C
• rs1456729
• NM_004006.3:c.6290+18403A>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.6290+18403A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 110,418 control chromosomes in the GnomAD database, including 814 homozygotes. There are 3,837 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 0.12 (814 hom., 3837 hem., cov: 22)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 1 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004006.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.6290+18403A>G		intron	N/A	NP_003997.2
	DMD	NM_004009.3		c.6278+18403A>G		intron	N/A	NP_004000.1
	DMD	NM_000109.4		c.6266+18403A>G		intron	N/A	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.6290+18403A>G		intron	N/A	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.6278+18403A>G		intron	N/A	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.2258+18403A>G		intron	N/A	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.121 AC: 13381 AN: 110363 Hom.: 816 Cov.: 22

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.161

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0120

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.132

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.121 AC: 13373 AN: 110418 Hom.: 814 Cov.: 22 AF XY: 0.117 AC XY: 3837 AN XY: 32666

African (AFR) AF: 0.0262 AC: 796 AN: 30436

American (AMR) AF: 0.163 AC: 1690 AN: 10337

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 378 AN: 2635

East Asian (EAS) AF: 0.0121 AC: 42 AN: 3481

South Asian (SAS) AF: 0.125 AC: 322 AN: 2577

European-Finnish (FIN) AF: 0.161 AC: 933 AN: 5810

Middle Eastern (MID) AF: 0.121 AC: 26 AN: 214

European-Non Finnish (NFE) AF: 0.169 AC: 8905 AN: 52743

Other (OTH) AF: 0.114 AC: 172 AN: 1510

Alfa AF: 0.136 Hom.: 1152

Bravo AF: 0.116

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.1
DANN	Benign	0.62
PhyloP100		0.31
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: rs1456729; hg19: chrX-32287243;