rs193249735

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-32454654-T-A
• chrX-32454654-T-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_004006.3(DMD):​c.3603+8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,049,905 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000029 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD NM_004006.3 splice_region, intron
• Scores: Splicing: ADA: 0.0006414
• Clinical Significance: Not reported in ClinVar
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AD geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.3603+8A>T		splice_region_variant, intron_variant	Intron 26 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.3603+8A>T		splice_region_variant, intron_variant	Intron 26 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 108216 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000286 AC: 3 AN: 1049905 Hom.: 0 Cov.: 25 AF XY: 0.00000603 AC XY: 2 AN XY: 331613

African (AFR) AF: 0.00 AC: 0 AN: 24648

American (AMR) AF: 0.00 AC: 0 AN: 31356

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 49612

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3848

European-Non Finnish (NFE) AF: 0.00000368 AC: 3 AN: 815068

Other (OTH) AF: 0.00 AC: 0 AN: 44337

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 108216 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 31072

African (AFR) AF: 0.00 AC: 0 AN: 30057

American (AMR) AF: 0.00 AC: 0 AN: 10064

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3467

South Asian (SAS) AF: 0.00 AC: 0 AN: 2589

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 51789

Other (OTH) AF: 0.00 AC: 0 AN: 1455

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.1
DANN	Benign	0.69
PhyloP100		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00064
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: rs193249735; hg19: chrX-32472771;