chrX-32362879-C-T

Variant names:

• chrX-32362879-C-T
• rs1801187
• NM_004006.3:c.5234G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004006.3(DMD):​c.5234G>A​(p.Arg1745His) variant causes a missense change. The variant allele was found at a frequency of 0.477 in 1,207,521 control chromosomes in the GnomAD database, including 96,016 homozygotes. There are 192,221 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1745C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (7187 hom., 12673 hem., cov: 22)
  • Exomes 𝑓: 0.49 (88829 hom. 179548 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 4.17
• Publications: 48 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1590453E-5).
• BP6: Variant X-32362879-C-T is Benign according to our data. Variant chrX-32362879-C-T is described in ClinVar as Benign. ClinVar VariationId is 94657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

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.5234G>A	p.Arg1745His	missense	Exon 37 of 79	NP_003997.2
	DMD	NM_004009.3		c.5222G>A	p.Arg1741His	missense	Exon 37 of 79	NP_004000.1
	DMD	NM_000109.4		c.5210G>A	p.Arg1737His	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.5234G>A	p.Arg1745His	missense	Exon 37 of 79	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.5222G>A	p.Arg1741His	missense	Exon 37 of 79	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.1202G>A	p.Arg401His	missense	Exon 9 of 51	ENSP00000479270.2

Frequencies

GnomAD3 genomes AF: 0.385 AC: 42289 AN: 109787 Hom.: 7190 Cov.: 22

Gnomad AFR AF: 0.0832

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.419

GnomAD2 exomes AF: 0.528 AC: 96466 AN: 182810 AF XY: 0.533

Gnomad AFR exome AF: 0.0726

Gnomad AMR exome AF: 0.728

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.735

Gnomad FIN exome AF: 0.529

Gnomad NFE exome AF: 0.477

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.486 AC: 533313 AN: 1097681 Hom.: 88829 Cov.: 34 AF XY: 0.494 AC XY: 179548 AN XY: 363113

African (AFR) AF: 0.0666 AC: 1758 AN: 26390

American (AMR) AF: 0.711 AC: 25021 AN: 35186

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 8686 AN: 19383

East Asian (EAS) AF: 0.685 AC: 20687 AN: 30197

South Asian (SAS) AF: 0.662 AC: 35836 AN: 54144

European-Finnish (FIN) AF: 0.522 AC: 21154 AN: 40503

Middle Eastern (MID) AF: 0.488 AC: 2017 AN: 4133

European-Non Finnish (NFE) AF: 0.471 AC: 396310 AN: 841668

Other (OTH) AF: 0.474 AC: 21844 AN: 46077

GnomAD4 genome AF: 0.385 AC: 42276 AN: 109840 Hom.: 7187 Cov.: 22 AF XY: 0.394 AC XY: 12673 AN XY: 32130

African (AFR) AF: 0.0830 AC: 2522 AN: 30397

American (AMR) AF: 0.581 AC: 5909 AN: 10172

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1123 AN: 2614

East Asian (EAS) AF: 0.711 AC: 2437 AN: 3427

South Asian (SAS) AF: 0.655 AC: 1691 AN: 2581

European-Finnish (FIN) AF: 0.513 AC: 2890 AN: 5629

Middle Eastern (MID) AF: 0.395 AC: 85 AN: 215

European-Non Finnish (NFE) AF: 0.470 AC: 24713 AN: 52634

Other (OTH) AF: 0.415 AC: 622 AN: 1497

Alfa AF: 0.445 Hom.: 64748

Bravo AF: 0.381

TwinsUK AF: 0.479 AC: 1775

ALSPAC AF: 0.472 AC: 1363

ESP6500AA AF: 0.0806 AC: 309

ESP6500EA AF: 0.477 AC: 3209

ExAC AF: 0.516 AC: 62654

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	Duchenne muscular dystrophy (3)
-	-	3	not provided (3)
-	-	2	Dilated cardiomyopathy 3B (2)
-	-	1	Cardiovascular phenotype (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	0.079
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.000012	T
MetaSVM	Benign	-0.90	T
PhyloP100		4.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.15
MPC		0.071
ClinPred		0.020	T
GERP RS		5.2
gMVP		0.37
Mutation Taster		=93/7	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: rs1801187; hg19: chrX-32380996; COSMIC: COSV63739824; COSMIC: COSV63739824;