rs5972599

Variant names:

• chrX-32573624-G-A
• rs5972599
• NM_004006.3:c.1718C>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.1718C>T​(p.Ala573Val) variant causes a missense change. The variant allele was found at a frequency of 0.000802 in 1,206,911 control chromosomes in the GnomAD database, including 4 homozygotes. There are 274 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A573A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., 125 hem., cov: 23)
  • Exomes 𝑓: 0.00047 (1 hom. 149 hem.)
• Consequence: DMD NM_004006.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.45
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• 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=0.00982815).
• BP6: Variant X-32573624-G-A is Benign according to our data. Variant chrX-32573624-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226566.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 = 0.00405 (454/112053) while in subpopulation AFR AF = 0.014 (433/30855). AF 95% confidence interval is 0.0129. There are 3 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 454 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.1718C>T	p.Ala573Val	missense	Exon 15 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1706C>T	p.Ala569Val	missense	Exon 15 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1694C>T	p.Ala565Val	missense	Exon 15 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.1718C>T	p.Ala573Val	missense	Exon 15 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1694C>T	p.Ala565Val	missense	Exon 15 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.362C>T	p.Ala121Val	missense	Exon 5 of 5	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 455 AN: 111999 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00162

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00127 AC: 233 AN: 183132 AF XY: 0.00102

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000548

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.000469 AC: 514 AN: 1094858 Hom.: 1 Cov.: 29 AF XY: 0.000414 AC XY: 149 AN XY: 360316

African (AFR) AF: 0.0166 AC: 436 AN: 26331

American (AMR) AF: 0.000625 AC: 22 AN: 35179

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19364

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.0000925 AC: 5 AN: 54074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.000728 AC: 3 AN: 4121

European-Non Finnish (NFE) AF: 0.00000834 AC: 7 AN: 839113

Other (OTH) AF: 0.000892 AC: 41 AN: 45985

GnomAD4 genome AF: 0.00405 AC: 454 AN: 112053 Hom.: 3 Cov.: 23 AF XY: 0.00365 AC XY: 125 AN XY: 34251

African (AFR) AF: 0.0140 AC: 433 AN: 30855

American (AMR) AF: 0.00162 AC: 17 AN: 10518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3587

South Asian (SAS) AF: 0.000371 AC: 1 AN: 2692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6095

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53238

Other (OTH) AF: 0.00198 AC: 3 AN: 1515

Alfa AF: 0.00131 Hom.: 62

Bravo AF: 0.00522

ESP6500AA AF: 0.0144 AC: 55

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00134 AC: 162

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (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	0.083
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.95	T
PhyloP100		4.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.051	T
Sift4G	Benign	0.16	T
Polyphen		0.0	B
Vest4		0.080
MVP		0.49
MPC		0.020
ClinPred		0.0092	T
GERP RS		3.4
gMVP		0.093
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5972599; hg19: chrX-32591741;