rs140919039

Variant names:

• chrX-32573530-G-A
• rs140919039
• NM_004006.3:c.1812C>T

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.1812C>T​(p.Ala604Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,203,255 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 58 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., 23 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 35 hem.)
• Consequence: DMD NM_004006.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0005818
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0590
• 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: 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=-0.84).
• BP6: Variant X-32573530-G-A is Benign according to our data. Variant chrX-32573530-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.059 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000618 (69/111633) while in subpopulation AFR AF = 0.00198 (61/30749). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 69 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.1812C>T	p.Ala604Ala	splice_region synonymous	Exon 15 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.1800C>T	p.Ala600Ala	splice_region synonymous	Exon 15 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.1788C>T	p.Ala596Ala	splice_region 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.1812C>T	p.Ala604Ala	splice_region synonymous	Exon 15 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.1788C>T	p.Ala596Ala	splice_region synonymous	Exon 15 of 18	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.1800C>T	p.Ala600Ala	splice_region synonymous	Exon 15 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 69 AN: 111579 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.000268 AC: 49 AN: 182931 AF XY: 0.000237

Gnomad AFR exome AF: 0.00243

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000859

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000106 AC: 116 AN: 1091622 Hom.: 0 Cov.: 29 AF XY: 0.0000979 AC XY: 35 AN XY: 357544

African (AFR) AF: 0.00259 AC: 68 AN: 26259

American (AMR) AF: 0.000199 AC: 7 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19331

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30151

South Asian (SAS) AF: 0.0000556 AC: 3 AN: 53971

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3996

European-Non Finnish (NFE) AF: 0.0000299 AC: 25 AN: 836373

Other (OTH) AF: 0.000262 AC: 12 AN: 45857

GnomAD4 genome AF: 0.000618 AC: 69 AN: 111633 Hom.: 0 Cov.: 23 AF XY: 0.000679 AC XY: 23 AN XY: 33863

African (AFR) AF: 0.00198 AC: 61 AN: 30749

American (AMR) AF: 0.000191 AC: 2 AN: 10489

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.000376 AC: 1 AN: 2663

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53133

Other (OTH) AF: 0.00196 AC: 3 AN: 1529

Alfa AF: 0.000181 Hom.: 3

Bravo AF: 0.000616

EpiCase AF: 0.000327

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	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	-0.84
CADD	Benign	0.30
DANN	Benign	0.20
PhyloP100		0.059
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00058
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.040		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: rs140919039; hg19: chrX-32591647; COSMIC: COSV55903484; COSMIC: COSV55903484;