NM_004006.3:c.1813-222G>A

Variant names:

• chrX-32566103-C-T
• rs190172920
• NM_004006.3:c.1813-222G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004006.3(DMD):​c.1813-222G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000822 in 111,923 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 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 0.00082 (0 hom., 25 hem., cov: 23)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.652
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.94).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000822 (92/111923) while in subpopulation NFE AF = 0.00143 (76/53180). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 92 XL,AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.1813-222G>A		intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1801-222G>A		intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.1789-222G>A		intron	N/A	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.1813-222G>A		intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1789-222G>A		intron	N/A	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.1801-222G>A		intron	N/A	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.000813 AC: 91 AN: 111868 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000381

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000367

Gnomad FIN AF: 0.000334

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00198

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

GnomAD4 genome AF: 0.000822 AC: 92 AN: 111923 Hom.: 0 Cov.: 23 AF XY: 0.000732 AC XY: 25 AN XY: 34151

African (AFR) AF: 0.000194 AC: 6 AN: 30894

American (AMR) AF: 0.000381 AC: 4 AN: 10500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.000368 AC: 1 AN: 2716

European-Finnish (FIN) AF: 0.000334 AC: 2 AN: 5989

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00143 AC: 76 AN: 53180

Other (OTH) AF: 0.00196 AC: 3 AN: 1534

Alfa AF: 0.000702 Hom.: 2

Bravo AF: 0.000714

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.081
DANN	Benign	0.21
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism

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: rs190172920; hg19: chrX-32584220;