rs34102501

Variant names:

• chrX-32362931-G-A
• rs34102501
• NM_004006.3:c.5182C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004006.3(DMD):​c.5182C>T​(p.Arg1728Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000549 in 1,208,526 control chromosomes in the GnomAD database, including 5 homozygotes. There are 181 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1728H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., 96 hem., cov: 22)
  • Exomes 𝑓: 0.00031 (2 hom. 85 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:16
• Conservation: PhyloP100: 5.09
• Publications: 3 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0078805685).
• BP6: Variant X-32362931-G-A is Benign according to our data. Variant chrX-32362931-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94656.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00295 (328/111112) while in subpopulation AFR AF = 0.00965 (295/30577). AF 95% confidence interval is 0.00874. There are 3 homozygotes in GnomAd4. There are 96 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 328 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.5182C>T	p.Arg1728Cys	missense	Exon 37 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.5170C>T	p.Arg1724Cys	missense	Exon 37 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.5158C>T	p.Arg1720Cys	missense	Exon 37 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.5182C>T	p.Arg1728Cys	missense	Exon 37 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.5170C>T	p.Arg1724Cys	missense	Exon 37 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.1150C>T	p.Arg384Cys	missense	Exon 9 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 327 AN: 111055 Hom.: 3 Cov.: 22

Gnomad AFR AF: 0.00964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00251

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000377

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.000776 AC: 141 AN: 181795 AF XY: 0.000376

Gnomad AFR exome AF: 0.00954

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000742

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.000306 AC: 336 AN: 1097414 Hom.: 2 Cov.: 31 AF XY: 0.000234 AC XY: 85 AN XY: 362854

African (AFR) AF: 0.0100 AC: 264 AN: 26389

American (AMR) AF: 0.000654 AC: 23 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30162

South Asian (SAS) AF: 0.00 AC: 0 AN: 54090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40493

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4129

European-Non Finnish (NFE) AF: 0.0000214 AC: 18 AN: 841552

Other (OTH) AF: 0.000651 AC: 30 AN: 46074

GnomAD4 genome AF: 0.00295 AC: 328 AN: 111112 Hom.: 3 Cov.: 22 AF XY: 0.00288 AC XY: 96 AN XY: 33330

African (AFR) AF: 0.00965 AC: 295 AN: 30577

American (AMR) AF: 0.00251 AC: 26 AN: 10353

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3515

South Asian (SAS) AF: 0.00 AC: 0 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000377 AC: 2 AN: 53062

Other (OTH) AF: 0.00332 AC: 5 AN: 1507

Alfa AF: 0.00297 Hom.: 59

Bravo AF: 0.00374

ESP6500AA AF: 0.00861 AC: 33

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000816 AC: 99

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 3B (1)
-	-	1	DMD-related disorder (1)
-	-	1	Duchenne muscular dystrophy (1)
-	-	1	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.71	T
PhyloP100		5.1
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.033	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.57
MPC		0.093
ClinPred		0.030	T
GERP RS		5.2
gMVP		0.21
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs34102501; hg19: chrX-32381048; COSMIC: COSV105915513; COSMIC: COSV105915513;