rs137905486

Variant names:

• chrX-31323657-C-T
• rs137905486
• NM_004006.3:c.9165G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_004006.3(DMD):​c.9165G>A​(p.Thr3055Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000804 in 1,206,601 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 26 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000066 (0 hom. 23 hem.)
• Consequence: DMD NM_004006.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005395
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.35
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.018).
• BP6: Variant X-31323657-C-T is Benign according to our data. Variant chrX-31323657-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286909.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BS2: High AC in GnomAd4 at 25 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.9165G>A	p.Thr3055Thr	splice_region synonymous	Exon 62 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.9153G>A	p.Thr3051Thr	splice_region synonymous	Exon 62 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.9141G>A	p.Thr3047Thr	splice_region synonymous	Exon 62 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.9165G>A	p.Thr3055Thr	splice_region synonymous	Exon 62 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.9153G>A	p.Thr3051Thr	splice_region synonymous	Exon 62 of 79	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.5133G>A	p.Thr1711Thr	splice_region synonymous	Exon 34 of 51	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes AF: 0.000225 AC: 25 AN: 111137 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000590

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000837

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000755

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 37 AN: 180252 AF XY: 0.0000925

Gnomad AFR exome AF: 0.000924

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000657 AC: 72 AN: 1095416 Hom.: 0 Cov.: 29 AF XY: 0.0000637 AC XY: 23 AN XY: 360874

African (AFR) AF: 0.000417 AC: 11 AN: 26360

American (AMR) AF: 0.0000854 AC: 3 AN: 35139

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19343

East Asian (EAS) AF: 0.000596 AC: 18 AN: 30183

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53775

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.0000417 AC: 35 AN: 840039

Other (OTH) AF: 0.0000870 AC: 4 AN: 46002

GnomAD4 genome AF: 0.000225 AC: 25 AN: 111185 Hom.: 0 Cov.: 23 AF XY: 0.0000896 AC XY: 3 AN XY: 33469

African (AFR) AF: 0.000588 AC: 18 AN: 30590

American (AMR) AF: 0.00 AC: 0 AN: 10420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.000839 AC: 3 AN: 3575

South Asian (SAS) AF: 0.00 AC: 0 AN: 2637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.0000755 AC: 4 AN: 53007

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.000124 Hom.: 3

Bravo AF: 0.000196

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Cardiovascular phenotype (1)
-	-	1	DMD-related disorder (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	-0.55
CADD	Benign	4.3
DANN	Benign	0.80
PhyloP100		1.4
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.0020
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: rs137905486; hg19: chrX-31341774;