rs61733587

Variant names:

• chrX-32595805-A-T
• rs61733587
• NM_004006.3:c.1554T>A

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.1554T>A​(p.Asp518Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,205,108 control chromosomes in the GnomAD database, including 29 homozygotes. There are 652 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. D518G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (18 hom., 329 hem., cov: 23)
  • Exomes 𝑓: 0.0010 (11 hom. 323 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.56
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007825434).
• BP6: Variant X-32595805-A-T is Benign according to our data. Variant chrX-32595805-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94473.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 = 0.0104 (1168/112299) while in subpopulation AFR AF = 0.0362 (1121/30948). AF 95% confidence interval is 0.0345. There are 18 homozygotes in GnomAd4. There are 329 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1168 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.1554T>A	p.Asp518Glu	missense	Exon 13 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1542T>A	p.Asp514Glu	missense	Exon 13 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1530T>A	p.Asp510Glu	missense	Exon 13 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.1554T>A	p.Asp518Glu	missense	Exon 13 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1530T>A	p.Asp510Glu	missense	Exon 13 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.247-21959T>A		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1167 AN: 112243 Hom.: 18 Cov.: 23

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

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: 0.0000751

Gnomad OTH AF: 0.00462

GnomAD2 exomes AF: 0.00287 AC: 526 AN: 183134 AF XY: 0.00219

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00103 AC: 1126 AN: 1092809 Hom.: 11 Cov.: 28 AF XY: 0.000902 AC XY: 323 AN XY: 358283

African (AFR) AF: 0.0362 AC: 953 AN: 26305

American (AMR) AF: 0.00162 AC: 57 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19350

East Asian (EAS) AF: 0.00 AC: 0 AN: 30154

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54001

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.000485 AC: 2 AN: 4123

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 837260

Other (OTH) AF: 0.00224 AC: 103 AN: 45902

GnomAD4 genome AF: 0.0104 AC: 1168 AN: 112299 Hom.: 18 Cov.: 23 AF XY: 0.00954 AC XY: 329 AN XY: 34469

African (AFR) AF: 0.0362 AC: 1121 AN: 30948

American (AMR) AF: 0.00340 AC: 36 AN: 10586

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3582

South Asian (SAS) AF: 0.00 AC: 0 AN: 2725

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6105

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000751 AC: 4 AN: 53262

Other (OTH) AF: 0.00456 AC: 7 AN: 1534

Alfa AF: 0.00595 Hom.: 32

Bravo AF: 0.0125

ESP6500AA AF: 0.0350 AC: 134

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00331 AC: 402

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.75	T
PhyloP100		1.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.63
MutPred		0.37		Gain of catalytic residue at D518 (P = 0.0711)
MVP		0.86
MPC		0.099
ClinPred		0.023	T
GERP RS		2.1
gMVP		0.35
Mutation Taster		=97/3	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: rs61733587; hg19: chrX-32613922;