rs1921961

Variant names:

• chrX-31578850-C-T
• rs1921961
• NM_004006.3:c.8217+48823G>A

Variant summary

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

The NM_004006.3(DMD):​c.8217+48823G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 111,232 control chromosomes in the GnomAD database, including 4,377 homozygotes. There are 10,358 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 0.32 (4377 hom., 10358 hem., cov: 23)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.435
• Publications: 0 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

ENSG00000310315 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.404 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.8217+48823G>A		intron_variant	Intron 55 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.8217+48823G>A		intron_variant	Intron 55 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.323 AC: 35914 AN: 111179 Hom.: 4373 Cov.: 23

Gnomad AFR AF: 0.409

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.272

Gnomad EAS AF: 0.349

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.279

Gnomad OTH AF: 0.357

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

GnomAD4 genome AF: 0.323 AC: 35975 AN: 111232 Hom.: 4377 Cov.: 23 AF XY: 0.309 AC XY: 10358 AN XY: 33476

African (AFR) AF: 0.410 AC: 12541 AN: 30562

American (AMR) AF: 0.378 AC: 3974 AN: 10512

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 720 AN: 2644

East Asian (EAS) AF: 0.349 AC: 1229 AN: 3526

South Asian (SAS) AF: 0.232 AC: 611 AN: 2630

European-Finnish (FIN) AF: 0.220 AC: 1314 AN: 5967

Middle Eastern (MID) AF: 0.379 AC: 81 AN: 214

European-Non Finnish (NFE) AF: 0.279 AC: 14806 AN: 52987

Other (OTH) AF: 0.361 AC: 547 AN: 1514

Alfa AF: 0.308 Hom.: 2164

Bravo AF: 0.346

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.64
DANN	Benign	0.65
PhyloP100		-0.43
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: rs1921961; hg19: chrX-31596967;