X-32573814-T-C

Variant names:

• chrX-32573814-T-C
• rs5927083
• NM_004006.3:c.1635A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004006.3(DMD):​c.1635A>G​(p.Arg545Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,208,966 control chromosomes in the GnomAD database, including 6,324 homozygotes. There are 48,417 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (698 hom., 3924 hem., cov: 22)
  • Exomes 𝑓: 0.12 (5626 hom. 44493 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -0.219
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-32573814-T-C is Benign according to our data. Variant chrX-32573814-T-C is described in ClinVar as Benign. ClinVar VariationId is 94476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.219 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 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.1635A>G	p.Arg545Arg	synonymous	Exon 14 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1623A>G	p.Arg541Arg	synonymous	Exon 14 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1611A>G	p.Arg537Arg	synonymous	Exon 14 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.1635A>G	p.Arg545Arg	synonymous	Exon 14 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1611A>G	p.Arg537Arg	synonymous	Exon 14 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.279A>G	p.Arg93Arg	synonymous	Exon 4 of 5	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes AF: 0.125 AC: 14005 AN: 111659 Hom.: 699 Cov.: 22

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0760

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0875

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.126

GnomAD2 exomes AF: 0.107 AC: 19408 AN: 181905 AF XY: 0.110

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.0457

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.0191

Gnomad FIN exome AF: 0.0985

Gnomad NFE exome AF: 0.127

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.121 AC: 132744 AN: 1097254 Hom.: 5626 Cov.: 31 AF XY: 0.123 AC XY: 44493 AN XY: 362870

African (AFR) AF: 0.161 AC: 4262 AN: 26395

American (AMR) AF: 0.0500 AC: 1758 AN: 35149

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 3066 AN: 19377

East Asian (EAS) AF: 0.0115 AC: 348 AN: 30190

South Asian (SAS) AF: 0.121 AC: 6557 AN: 54058

European-Finnish (FIN) AF: 0.102 AC: 4111 AN: 40480

Middle Eastern (MID) AF: 0.177 AC: 732 AN: 4136

European-Non Finnish (NFE) AF: 0.126 AC: 106260 AN: 841404

Other (OTH) AF: 0.123 AC: 5650 AN: 46065

GnomAD4 genome AF: 0.125 AC: 14006 AN: 111712 Hom.: 698 Cov.: 22 AF XY: 0.116 AC XY: 3924 AN XY: 33900

African (AFR) AF: 0.158 AC: 4863 AN: 30694

American (AMR) AF: 0.0757 AC: 797 AN: 10526

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 380 AN: 2644

East Asian (EAS) AF: 0.0140 AC: 50 AN: 3559

South Asian (SAS) AF: 0.120 AC: 323 AN: 2681

European-Finnish (FIN) AF: 0.0875 AC: 530 AN: 6058

Middle Eastern (MID) AF: 0.147 AC: 32 AN: 218

European-Non Finnish (NFE) AF: 0.127 AC: 6760 AN: 53128

Other (OTH) AF: 0.124 AC: 189 AN: 1521

Alfa AF: 0.131 Hom.: 12928

Bravo AF: 0.126

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Duchenne muscular dystrophy (2)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 3B (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
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
DANN	Benign	0.55
PhyloP100		-0.22
Mutation Taster		=99/1	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: rs5927083; hg19: chrX-32591931; COSMIC: COSV55865224;