rs142153424

Variant names:

• chrX-31774026-A-G
• rs142153424
• NM_004006.3:c.7476T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004006.3(DMD):​c.7476T>C​(p.Val2492Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,207,387 control chromosomes in the GnomAD database, including 8 homozygotes. There are 325 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., 159 hem., cov: 21)
  • Exomes 𝑓: 0.00060 (3 hom. 166 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.416
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.029).
• BP6: Variant X-31774026-A-G is Benign according to our data. Variant chrX-31774026-A-G is described in ClinVar as Benign. ClinVar VariationId is 94765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.416 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00581 (635/109327) while in subpopulation AFR AF = 0.0199 (597/29982). AF 95% confidence interval is 0.0186. There are 5 homozygotes in GnomAd4. There are 159 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High AC in GnomAd4 at 635 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.7476T>C	p.Val2492Val	synonymous	Exon 51 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.7464T>C	p.Val2488Val	synonymous	Exon 51 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.7452T>C	p.Val2484Val	synonymous	Exon 51 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.7476T>C	p.Val2492Val	synonymous	Exon 51 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000471779.1	TSL:1	n.*140T>C		non_coding_transcript_exon	Exon 2 of 3	ENSP00000417075.1	A0A0C4DH61
	DMD	ENST00000471779.1	TSL:1	n.*140T>C		3_prime_UTR	Exon 2 of 3	ENSP00000417075.1	A0A0C4DH61

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 634 AN: 109270 Hom.: 5 Cov.: 21

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00239

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: 0.000114

Gnomad OTH AF: 0.00547

GnomAD2 exomes AF: 0.00159 AC: 291 AN: 183219 AF XY: 0.000886

Gnomad AFR exome AF: 0.0200

Gnomad AMR exome AF: 0.000730

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: 0.00111

GnomAD4 exome AF: 0.000597 AC: 655 AN: 1098060 Hom.: 3 Cov.: 31 AF XY: 0.000457 AC XY: 166 AN XY: 363456

African (AFR) AF: 0.0205 AC: 540 AN: 26396

American (AMR) AF: 0.000909 AC: 32 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.0000554 AC: 3 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40528

Middle Eastern (MID) AF: 0.000967 AC: 4 AN: 4136

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 841988

Other (OTH) AF: 0.00148 AC: 68 AN: 46091

GnomAD4 genome AF: 0.00581 AC: 635 AN: 109327 Hom.: 5 Cov.: 21 AF XY: 0.00503 AC XY: 159 AN XY: 31609

African (AFR) AF: 0.0199 AC: 597 AN: 29982

American (AMR) AF: 0.00239 AC: 24 AN: 10042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3464

South Asian (SAS) AF: 0.00 AC: 0 AN: 2476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5635

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.000114 AC: 6 AN: 52721

Other (OTH) AF: 0.00539 AC: 8 AN: 1483

Alfa AF: 0.00268 Hom.: 17

Bravo AF: 0.00707

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	not provided (2)
-	-	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	Duchenne muscular dystrophy;C0917713:Becker muscular dystrophy;C3668940:Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.0
DANN	Benign	0.72
PhyloP100		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs142153424; hg19: chrX-31792143;