X-32849828-TA-TAA

Variant names:

• chrX-32849828-T-TA
• rs3834997
• NM_004006.3:c.94-9dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004006.3(DMD):​c.94-9dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0967 in 1,126,276 control chromosomes in the GnomAD database, including 3,909 homozygotes. There are 29,449 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (376 hom., 2657 hem., cov: 20)
  • Exomes 𝑓: 0.097 (3533 hom. 26792 hem.)
• Consequence: DMD NM_004006.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.00
• 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• 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 -16 ACMG points.

• BP6: Variant X-32849828-T-TA is Benign according to our data. Variant chrX-32849828-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

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.94-9dupT		intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.82-9dupT		intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.70-9dupT		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.94-9_94-8insT		intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.70-9_70-8insT		intron	N/A	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000378677.6	TSL:5	c.82-9_82-8insT		intron	N/A	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.0902 AC: 9962 AN: 110447 Hom.: 377 Cov.: 20

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.247

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0771

Gnomad MID AF: 0.173

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0974

GnomAD2 exomes AF: 0.0923 AC: 16478 AN: 178466 AF XY: 0.0858

Gnomad AFR exome AF: 0.0445

Gnomad AMR exome AF: 0.0485

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.133

Gnomad FIN exome AF: 0.0842

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.0974 AC: 98914 AN: 1015777 Hom.: 3533 Cov.: 23 AF XY: 0.0907 AC XY: 26792 AN XY: 295315

African (AFR) AF: 0.0445 AC: 1112 AN: 24966

American (AMR) AF: 0.0496 AC: 1731 AN: 34888

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 3115 AN: 18604

East Asian (EAS) AF: 0.102 AC: 3017 AN: 29645

South Asian (SAS) AF: 0.0699 AC: 3631 AN: 51930

European-Finnish (FIN) AF: 0.0832 AC: 3350 AN: 40255

Middle Eastern (MID) AF: 0.125 AC: 490 AN: 3927

European-Non Finnish (NFE) AF: 0.102 AC: 78103 AN: 768197

Other (OTH) AF: 0.101 AC: 4365 AN: 43365

GnomAD4 genome AF: 0.0901 AC: 9961 AN: 110499 Hom.: 376 Cov.: 20 AF XY: 0.0809 AC XY: 2657 AN XY: 32857

African (AFR) AF: 0.0469 AC: 1430 AN: 30497

American (AMR) AF: 0.0768 AC: 793 AN: 10320

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 469 AN: 2622

East Asian (EAS) AF: 0.125 AC: 435 AN: 3482

South Asian (SAS) AF: 0.0629 AC: 166 AN: 2638

European-Finnish (FIN) AF: 0.0771 AC: 449 AN: 5824

Middle Eastern (MID) AF: 0.162 AC: 34 AN: 210

European-Non Finnish (NFE) AF: 0.111 AC: 5874 AN: 52758

Other (OTH) AF: 0.0982 AC: 145 AN: 1477

Alfa AF: 0.0792 Hom.: 596

Bravo AF: 0.0899

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Duchenne muscular dystrophy (2)
-	-	1	Dilated cardiomyopathy 3B (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs3834997; hg19: chrX-32867945; COSMIC: COSV99927200; COSMIC: COSV99927200;