chrX-32595856-T-C

Variant names:

• chrX-32595856-T-C
• rs770464589
• NM_004006.3:c.1503A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_004006.3(DMD):​c.1503A>G​(p.Glu501Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000051 in 1,195,391 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000052 (0 hom. 20 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.578
• 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: 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-32595856-T-C is Benign according to our data. Variant chrX-32595856-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.578 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.1503A>G	p.Glu501Glu	synonymous	Exon 13 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1491A>G	p.Glu497Glu	synonymous	Exon 13 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1479A>G	p.Glu493Glu	synonymous	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.1503A>G	p.Glu501Glu	synonymous	Exon 13 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1479A>G	p.Glu493Glu	synonymous	Exon 13 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.247-22010A>G		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111863 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000137 AC: 25 AN: 183123 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000621

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000979

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000517 AC: 56 AN: 1083477 Hom.: 0 Cov.: 27 AF XY: 0.0000572 AC XY: 20 AN XY: 349823

African (AFR) AF: 0.00 AC: 0 AN: 26127

American (AMR) AF: 0.000569 AC: 20 AN: 35179

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19289

East Asian (EAS) AF: 0.00 AC: 0 AN: 30119

South Asian (SAS) AF: 0.00 AC: 0 AN: 53769

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

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4108

European-Non Finnish (NFE) AF: 0.0000374 AC: 31 AN: 828733

Other (OTH) AF: 0.0000877 AC: 4 AN: 45635

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111914 Hom.: 0 Cov.: 23 AF XY: 0.0000587 AC XY: 2 AN XY: 34078

African (AFR) AF: 0.00 AC: 0 AN: 30893

American (AMR) AF: 0.000286 AC: 3 AN: 10502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3546

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6007

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53208

Other (OTH) AF: 0.00 AC: 0 AN: 1521

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000193

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DMD-related disorder (1)
-	-	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
BayesDel_noAF	Benign	-0.54
CADD	Benign	3.4
DANN	Benign	0.58
PhyloP100		0.58
Mutation Taster		=100/0	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: rs770464589; hg19: chrX-32613973;