X-32454654-T-C

Variant names:

• chrX-32454654-T-C
• rs193249735
• NM_004006.3:c.3603+8A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004006.3(DMD):​c.3603+8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,158,149 control chromosomes in the GnomAD database, including 22 homozygotes. There are 371 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 0.0068 (14 hom., 180 hem., cov: 22)
  • Exomes 𝑓: 0.00068 (8 hom. 191 hem.)
• Consequence: DMD NM_004006.3 splice_region, intron
• Scores: Splicing: ADA: 0.0006101
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.860
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-32454654-T-C is Benign according to our data. Variant chrX-32454654-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00681 (737/108248) while in subpopulation AFR AF = 0.0233 (702/30113). AF 95% confidence interval is 0.0219. There are 14 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 737 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.3603+8A>G		splice_region intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.3591+8A>G		splice_region intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.3579+8A>G		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.3603+8A>G		splice_region intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.3591+8A>G		splice_region intron	N/A	ENSP00000367948.2	P11532-11
	DMD	ENST00000420596.5	TSL:5	c.94-89455A>G		intron	N/A	ENSP00000399897.1	Q14172

Frequencies

GnomAD3 genomes AF: 0.00682 AC: 738 AN: 108214 Hom.: 14 Cov.: 22

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00248

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: 0.0000193

Gnomad OTH AF: 0.00619

GnomAD2 exomes AF: 0.00204 AC: 325 AN: 159242 AF XY: 0.00125

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000679 AC: 713 AN: 1049901 Hom.: 8 Cov.: 25 AF XY: 0.000576 AC XY: 191 AN XY: 331611

African (AFR) AF: 0.0235 AC: 579 AN: 24648

American (AMR) AF: 0.00156 AC: 49 AN: 31354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18578

East Asian (EAS) AF: 0.00 AC: 0 AN: 29838

South Asian (SAS) AF: 0.000101 AC: 5 AN: 49611

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32620

Middle Eastern (MID) AF: 0.00104 AC: 4 AN: 3848

European-Non Finnish (NFE) AF: 0.00000613 AC: 5 AN: 815067

Other (OTH) AF: 0.00160 AC: 71 AN: 44337

GnomAD4 genome AF: 0.00681 AC: 737 AN: 108248 Hom.: 14 Cov.: 22 AF XY: 0.00579 AC XY: 180 AN XY: 31114

African (AFR) AF: 0.0233 AC: 702 AN: 30113

American (AMR) AF: 0.00248 AC: 25 AN: 10075

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2588

East Asian (EAS) AF: 0.00 AC: 0 AN: 3455

South Asian (SAS) AF: 0.00 AC: 0 AN: 2576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000193 AC: 1 AN: 51782

Other (OTH) AF: 0.00611 AC: 9 AN: 1473

Alfa AF: 0.00386 Hom.: 20

Bravo AF: 0.00765

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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	-0.78
CADD	Benign	8.3
DANN	Benign	0.72
PhyloP100		0.86
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00061
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.070		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: rs193249735; hg19: chrX-32472771;