rs192176661

Variant names:

• chrX-32573533-C-T
• rs192176661
• NM_004006.3:c.1809G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-32573533-C-T
• chrX-32573533-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004006.3(DMD):​c.1809G>A​(p.Leu603Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,205,767 control chromosomes in the GnomAD database, including 1 homozygotes. There are 93 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 0.00027 (0 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00022 (1 hom. 84 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.213
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-32573533-C-T is Benign according to our data. Variant chrX-32573533-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 285219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.213 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000268 (30/111823) while in subpopulation EAS AF = 0.00785 (28/3567). AF 95% confidence interval is 0.00558. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 30 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.1809G>A	p.Leu603Leu	synonymous	Exon 15 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1797G>A	p.Leu599Leu	synonymous	Exon 15 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1785G>A	p.Leu595Leu	synonymous	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.1809G>A	p.Leu603Leu	synonymous	Exon 15 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1785G>A	p.Leu595Leu	synonymous	Exon 15 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.1797G>A	p.Leu599Leu	synonymous	Exon 15 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.000268 AC: 30 AN: 111769 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00783

Gnomad SAS AF: 0.000373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000705 AC: 129 AN: 182977 AF XY: 0.000562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00859

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000217 AC: 237 AN: 1093944 Hom.: 1 Cov.: 29 AF XY: 0.000234 AC XY: 84 AN XY: 359568

African (AFR) AF: 0.00 AC: 0 AN: 26311

American (AMR) AF: 0.00 AC: 0 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19356

East Asian (EAS) AF: 0.00620 AC: 187 AN: 30163

South Asian (SAS) AF: 0.000500 AC: 27 AN: 54030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4016

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 838449

Other (OTH) AF: 0.000305 AC: 14 AN: 45929

GnomAD4 genome AF: 0.000268 AC: 30 AN: 111823 Hom.: 0 Cov.: 23 AF XY: 0.000264 AC XY: 9 AN XY: 34049

African (AFR) AF: 0.00 AC: 0 AN: 30806

American (AMR) AF: 0.00 AC: 0 AN: 10492

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

East Asian (EAS) AF: 0.00785 AC: 28 AN: 3567

South Asian (SAS) AF: 0.000374 AC: 1 AN: 2672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5996

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

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53201

Other (OTH) AF: 0.00 AC: 0 AN: 1529

Alfa AF: 0.000179 Hom.: 1

Bravo AF: 0.000582

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (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	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.99
DANN	Benign	0.42
PhyloP100		0.21
Mutation Taster		=100/0	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: rs192176661; hg19: chrX-32591650;