rs745462674

Variant names:

• chrX-32389514-A-C
• rs745462674
• NM_004006.3:c.4505T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PP3_Moderate BP6 BS2_Supporting

The NM_004006.3(DMD):​c.4505T>G​(p.Leu1502Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000909 in 1,209,596 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1502L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000091 (0 hom. 4 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 9.10
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• BP6: Variant X-32389514-A-C is Benign according to our data. Variant chrX-32389514-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 570531.
• BS2: High AC in GnomAdExome4 at 10 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.4505T>G	p.Leu1502Arg	missense	Exon 32 of 79	NP_003997.2
	DMD	NM_004009.3		c.4493T>G	p.Leu1498Arg	missense	Exon 32 of 79	NP_004000.1
	DMD	NM_000109.4		c.4481T>G	p.Leu1494Arg	missense	Exon 32 of 79	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.4505T>G	p.Leu1502Arg	missense	Exon 32 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.4493T>G	p.Leu1498Arg	missense	Exon 32 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.473T>G	p.Leu158Arg	missense	Exon 4 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112070 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183091 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1097526 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 4 AN XY: 363172

African (AFR) AF: 0.00 AC: 0 AN: 26373

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30141

South Asian (SAS) AF: 0.00 AC: 0 AN: 54135

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40509

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841609

Other (OTH) AF: 0.00 AC: 0 AN: 46062

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112070 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34236

African (AFR) AF: 0.00 AC: 0 AN: 30847

American (AMR) AF: 0.00 AC: 0 AN: 10505

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6127

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53162

Other (OTH) AF: 0.00 AC: 0 AN: 1515

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Duchenne muscular dystrophy (1)
-	1	-	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	0.20	D
PhyloP100		9.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.68		Gain of catalytic residue at L1502 (P = 0.0135)
MVP		0.99
MPC		0.13
ClinPred		0.97	D
GERP RS		5.6
gMVP		0.84
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs745462674; hg19: chrX-32407631;