rs147931243

Variant names:

• chrX-32491521-A-G
• rs147931243
• NM_004006.3:c.2381-3T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.2381-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000693 in 1,203,022 control chromosomes in the GnomAD database, including 8 homozygotes. There are 271 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 0.00058 (0 hom., 23 hem., cov: 24)
  • Exomes 𝑓: 0.00070 (8 hom. 248 hem.)
• Consequence: DMD NM_004006.3 splice_region, intron
• Scores: Splicing: ADA: 0.006386
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.22
• 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

ENSG00000297605 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant X-32491521-A-G is Benign according to our data. Variant chrX-32491521-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 195492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000579 (65/112197) while in subpopulation EAS AF = 0.0173 (62/3590). AF 95% confidence interval is 0.0138. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 65 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.2381-3T>C		splice_region intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.2369-3T>C		splice_region intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.2357-3T>C		splice_region intron	N/A	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.2381-3T>C		splice_region intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.2369-3T>C		splice_region intron	N/A	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-126322T>C		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.000580 AC: 65 AN: 112143 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0172

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.000663

GnomAD2 exomes AF: 0.00151 AC: 259 AN: 171091 AF XY: 0.00146

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00164

Gnomad EAS exome AF: 0.0186

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000465

GnomAD4 exome AF: 0.000705 AC: 769 AN: 1090825 Hom.: 8 Cov.: 29 AF XY: 0.000695 AC XY: 248 AN XY: 356979

African (AFR) AF: 0.00 AC: 0 AN: 26164

American (AMR) AF: 0.00 AC: 0 AN: 34953

Ashkenazi Jewish (ASJ) AF: 0.000724 AC: 14 AN: 19331

East Asian (EAS) AF: 0.0241 AC: 721 AN: 29911

South Asian (SAS) AF: 0.000113 AC: 6 AN: 53278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39690

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4041

European-Non Finnish (NFE) AF: 0.0000131 AC: 11 AN: 837679

Other (OTH) AF: 0.000371 AC: 17 AN: 45778

GnomAD4 genome AF: 0.000579 AC: 65 AN: 112197 Hom.: 0 Cov.: 24 AF XY: 0.000669 AC XY: 23 AN XY: 34371

African (AFR) AF: 0.00 AC: 0 AN: 30907

American (AMR) AF: 0.00 AC: 0 AN: 10539

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.0173 AC: 62 AN: 3590

South Asian (SAS) AF: 0.00 AC: 0 AN: 2713

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6108

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

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53257

Other (OTH) AF: 0.000655 AC: 1 AN: 1527

Alfa AF: 0.000434 Hom.: 3

Bravo AF: 0.000695

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.9
DANN	Benign	0.95
PhyloP100		2.2
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0064
dbscSNV1_RF	Benign	0.062
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: rs147931243; hg19: chrX-32509638; COSMIC: COSV63756974;