chrX-32518039-C-A

Variant names:

• chrX-32518039-C-A
• rs151242451
• NM_004006.3:c.2261G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.2261G>T​(p.Gly754Val) variant causes a missense change. The variant allele was found at a frequency of 0.000188 in 1,208,580 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 66 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G754C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., 26 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 40 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.07
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010589749).
• BP6: Variant X-32518039-C-A is Benign according to our data. Variant chrX-32518039-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000924 (103/111509) while in subpopulation AFR AF = 0.00293 (90/30723). AF 95% confidence interval is 0.00244. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 103 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.2261G>T	p.Gly754Val	missense	Exon 18 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.2249G>T	p.Gly750Val	missense	Exon 18 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.2237G>T	p.Gly746Val	missense	Exon 18 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.2261G>T	p.Gly754Val	missense	Exon 18 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.2237G>T	p.Gly746Val	missense	Exon 18 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.2249G>T	p.Gly750Val	missense	Exon 18 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.000924 AC: 103 AN: 111455 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00294

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000954

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: 0.00

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.000295 AC: 54 AN: 183220 AF XY: 0.000221

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000113 AC: 124 AN: 1097071 Hom.: 0 Cov.: 29 AF XY: 0.000110 AC XY: 40 AN XY: 362495

African (AFR) AF: 0.00387 AC: 102 AN: 26382

American (AMR) AF: 0.000284 AC: 10 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30182

South Asian (SAS) AF: 0.00 AC: 0 AN: 54117

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841111

Other (OTH) AF: 0.000217 AC: 10 AN: 46057

GnomAD4 genome AF: 0.000924 AC: 103 AN: 111509 Hom.: 0 Cov.: 23 AF XY: 0.000771 AC XY: 26 AN XY: 33735

African (AFR) AF: 0.00293 AC: 90 AN: 30723

American (AMR) AF: 0.000952 AC: 10 AN: 10500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5969

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53061

Other (OTH) AF: 0.00197 AC: 3 AN: 1524

Alfa AF: 0.00299 Hom.: 9

Bravo AF: 0.00110

ESP6500AA AF: 0.00235 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Duchenne muscular dystrophy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DMD-related disorder (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
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.056	T
PhyloP100		6.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.21
Sift	Benign	0.20	T
Sift4G	Benign	0.077	T
Polyphen		1.0	D
Vest4		0.77
MVP		0.80
MPC		0.13
ClinPred		0.027	T
GERP RS		5.1
gMVP		0.33
Mutation Taster		=98/2	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: rs151242451; hg19: chrX-32536156;