rs139365076

Variant names:

• chrX-31496899-A-G
• rs139365076
• NM_004006.3:c.8436T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6 BP7 BS1 BS2

The NM_004006.3(DMD):​c.8436T>C​(p.Leu2812Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000959 in 1,209,738 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00052 (0 hom., 15 hem., cov: 24)
  • Exomes 𝑓: 0.000052 (0 hom. 20 hem.)
• Consequence: DMD NM_004006.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.343
• Publications: 1 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.223).
• BP6: Variant X-31496899-A-G is Benign according to our data. Variant chrX-31496899-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287025.
• BP7: Synonymous conserved (PhyloP=0.343 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000525 (59/112468) while in subpopulation AFR AF = 0.00187 (58/31003). AF 95% confidence interval is 0.00149. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 59 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.8436T>C	p.Leu2812Leu	synonymous	Exon 57 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.8424T>C	p.Leu2808Leu	synonymous	Exon 57 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.8412T>C	p.Leu2804Leu	synonymous	Exon 57 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.8436T>C	p.Leu2812Leu	synonymous	Exon 57 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.8424T>C	p.Leu2808Leu	synonymous	Exon 57 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.4404T>C	p.Leu1468Leu	synonymous	Exon 29 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.000525 AC: 59 AN: 112415 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000942

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000998 AC: 18 AN: 180430 AF XY: 0.0000769

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000519 AC: 57 AN: 1097270 Hom.: 0 Cov.: 31 AF XY: 0.0000551 AC XY: 20 AN XY: 362656

African (AFR) AF: 0.00167 AC: 44 AN: 26387

American (AMR) AF: 0.000284 AC: 10 AN: 35150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19367

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 53870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841627

Other (OTH) AF: 0.0000651 AC: 3 AN: 46068

GnomAD4 genome AF: 0.000525 AC: 59 AN: 112468 Hom.: 0 Cov.: 24 AF XY: 0.000433 AC XY: 15 AN XY: 34626

African (AFR) AF: 0.00187 AC: 58 AN: 31003

American (AMR) AF: 0.0000941 AC: 1 AN: 10627

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 2730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6149

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53316

Other (OTH) AF: 0.00 AC: 0 AN: 1531

Alfa AF: 0.000453 Hom.: 5

Bravo AF: 0.000695

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Duchenne muscular dystrophy (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	-0.61
CADD	Benign	5.5
DANN	Benign	0.78
PhyloP100		0.34
Mutation Taster		=98/2	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: rs139365076; hg19: chrX-31515016;