NM_004006.3:c.531-11_531-6dupATGTGT

Variant names:

• chrX-32809616-A-AACACAT
• rs758404687
• NM_004006.3:c.531-11_531-6dupATGTGT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_004006.3(DMD):​c.531-11_531-6dupATGTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,071,603 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.15
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-32809616-A-AACACAT is Benign according to our data. Variant chrX-32809616-A-AACACAT is described in ClinVar as Likely_benign. ClinVar VariationId is 455907.Status of the report is criteria_provided_single_submitter, 1 stars.

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.531-11_531-6dupATGTGT		splice_region intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.519-11_519-6dupATGTGT		splice_region intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.507-11_507-6dupATGTGT		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.531-6_531-5insATGTGT		splice_region intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.507-6_507-5insATGTGT		splice_region intron	N/A	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000447523.1	TSL:1	c.246+13678_246+13679insATGTGT		intron	N/A	ENSP00000395904.1	Q14174

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000280 AC: 3 AN: 1071603 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 338031

African (AFR) AF: 0.00 AC: 0 AN: 25905

American (AMR) AF: 0.00 AC: 0 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19200

East Asian (EAS) AF: 0.00 AC: 0 AN: 30086

South Asian (SAS) AF: 0.0000187 AC: 1 AN: 53519

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40405

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4065

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 818050

Other (OTH) AF: 0.0000221 AC: 1 AN: 45211

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	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
PhyloP100		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs758404687; hg19: chrX-32827733;