X-33211425-TA-TAA

Variant names:

• chrX-33211425-T-TA
• rs72470542
• NM_004006.3:c.-114dupT

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.-114dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,154,540 control chromosomes in the GnomAD database, including 330 homozygotes. There are 1,784 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (173 hom., 920 hem., cov: 21)
  • Exomes 𝑓: 0.0034 (157 hom. 864 hem.)
• Consequence: DMD NM_004006.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.681
• 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 -16 ACMG points.

• BP6: Variant X-33211425-T-TA is Benign according to our data. Variant chrX-33211425-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 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.-114dupT		5_prime_UTR	Exon 1 of 79	NP_003997.2	P11532-1
	DMD	NM_000109.4		c.7+127833dupT		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.-114dupT		5_prime_UTR	Exon 1 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.7+127833dupT		intron	N/A	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000682071.1		c.-645dupT		5_prime_UTR	Exon 1 of 17	ENSP00000508133.1	A0A804HKZ5

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 3658 AN: 111098 Hom.: 171 Cov.: 21

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0301

GnomAD4 exome AF: 0.00339 AC: 3540 AN: 1043387 Hom.: 157 Cov.: 30 AF XY: 0.00258 AC XY: 864 AN XY: 334613

African (AFR) AF: 0.120 AC: 2891 AN: 24140

American (AMR) AF: 0.00638 AC: 170 AN: 26639

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18036

East Asian (EAS) AF: 0.00 AC: 0 AN: 27166

South Asian (SAS) AF: 0.000330 AC: 16 AN: 48423

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37431

Middle Eastern (MID) AF: 0.00423 AC: 16 AN: 3783

European-Non Finnish (NFE) AF: 0.000108 AC: 88 AN: 814106

Other (OTH) AF: 0.00822 AC: 359 AN: 43663

GnomAD4 genome AF: 0.0330 AC: 3668 AN: 111153 Hom.: 173 Cov.: 21 AF XY: 0.0275 AC XY: 920 AN XY: 33413

African (AFR) AF: 0.115 AC: 3501 AN: 30461

American (AMR) AF: 0.0110 AC: 114 AN: 10382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3540

South Asian (SAS) AF: 0.00 AC: 0 AN: 2641

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6019

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53054

Other (OTH) AF: 0.0297 AC: 45 AN: 1513

Alfa AF: 0.0281 Hom.: 86

Bravo AF: 0.0389

Asia WGS AF: 0.00557 AC: 14 AN: 2522

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.68
Mutation Taster		=298/2	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: rs72470542; hg19: chrX-33229542;