rs143159113

Variant names:

• chrX-32343149-A-G
• rs143159113
• NM_004006.3:c.5724T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004006.3(DMD):​c.5724T>C​(p.Asp1908Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,208,713 control chromosomes in the GnomAD database, including 66 homozygotes. There are 940 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (33 hom., 436 hem., cov: 23)
  • Exomes 𝑓: 0.0016 (33 hom. 504 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.45
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-32343149-A-G is Benign according to our data. Variant chrX-32343149-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0152 (1695/111271) while in subpopulation AFR AF = 0.0502 (1539/30660). AF 95% confidence interval is 0.0481. There are 33 homozygotes in GnomAd4. There are 436 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1695 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.5724T>C	p.Asp1908Asp	synonymous	Exon 40 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.5712T>C	p.Asp1904Asp	synonymous	Exon 40 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.5700T>C	p.Asp1900Asp	synonymous	Exon 40 of 79	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.5724T>C	p.Asp1908Asp	synonymous	Exon 40 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.5712T>C	p.Asp1904Asp	synonymous	Exon 40 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.1692T>C	p.Asp564Asp	synonymous	Exon 12 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 1691 AN: 111222 Hom.: 33 Cov.: 23

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00189

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000381

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.000189

Gnomad OTH AF: 0.0141

GnomAD2 exomes AF: 0.00437 AC: 799 AN: 183017 AF XY: 0.00290

Gnomad AFR exome AF: 0.0503

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000184

Gnomad OTH exome AF: 0.00354

GnomAD4 exome AF: 0.00163 AC: 1787 AN: 1097442 Hom.: 33 Cov.: 29 AF XY: 0.00139 AC XY: 504 AN XY: 362950

African (AFR) AF: 0.0511 AC: 1349 AN: 26377

American (AMR) AF: 0.00404 AC: 142 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 28 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30155

South Asian (SAS) AF: 0.000185 AC: 10 AN: 54129

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40495

Middle Eastern (MID) AF: 0.00291 AC: 12 AN: 4128

European-Non Finnish (NFE) AF: 0.0000642 AC: 54 AN: 841533

Other (OTH) AF: 0.00417 AC: 192 AN: 46063

GnomAD4 genome AF: 0.0152 AC: 1695 AN: 111271 Hom.: 33 Cov.: 23 AF XY: 0.0130 AC XY: 436 AN XY: 33501

African (AFR) AF: 0.0502 AC: 1539 AN: 30660

American (AMR) AF: 0.0113 AC: 118 AN: 10436

Ashkenazi Jewish (ASJ) AF: 0.00189 AC: 5 AN: 2639

East Asian (EAS) AF: 0.00 AC: 0 AN: 3531

South Asian (SAS) AF: 0.000382 AC: 1 AN: 2618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6001

Middle Eastern (MID) AF: 0.00467 AC: 1 AN: 214

European-Non Finnish (NFE) AF: 0.000189 AC: 10 AN: 52970

Other (OTH) AF: 0.0139 AC: 21 AN: 1513

Alfa AF: 0.00976 Hom.: 49

Bravo AF: 0.0182

EpiCase AF: 0.0000546

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	-	1	Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.9
DANN	Benign	0.57
PhyloP100		3.4
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: rs143159113; hg19: chrX-32361266;