X-31119681-AACTT-AACTTACTT

Variant names:

• chrX-31119681-A-AACTT
• rs202154420
• NM_004006.3:c.*2234_*2237dupAAGT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_004006.3(DMD):​c.*2234_*2237dupAAGT variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0142 in 112,214 control chromosomes in the GnomAD database, including 14 homozygotes. There are 410 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.014 (14 hom., 408 hem., cov: 22)
  • Exomes 𝑓: 0.014 (0 hom. 2 hem.)
• Consequence: DMD NM_004006.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.26
• 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

ENSG00000297249 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0142 (1589/111918) while in subpopulation NFE AF = 0.0215 (1140/53086). AF 95% confidence interval is 0.0204. There are 14 homozygotes in GnomAd4. There are 408 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1589 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.*2234_*2237dupAAGT		3_prime_UTR	Exon 79 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.*2234_*2237dupAAGT		3_prime_UTR	Exon 79 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.*2234_*2237dupAAGT		3_prime_UTR	Exon 79 of 79	NP_000100.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.*2234_*2237dupAAGT		3_prime_UTR	Exon 79 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378723.7	TSL:1	c.*2148_*2151dupAAGT		3_prime_UTR	Exon 17 of 17	ENSP00000367997.3	P11532-6
	DMD	ENST00000378677.6	TSL:5	c.*2234_*2237dupAAGT		3_prime_UTR	Exon 79 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 1590 AN: 111869 Hom.: 14 Cov.: 22

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00587

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.0111

Gnomad SAS AF: 0.00366

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0113

GnomAD4 exome AF: 0.0135 AC: 4 AN: 296 Hom.: 0 Cov.: 0 AF XY: 0.0161 AC XY: 2 AN XY: 124

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0137 AC: 4 AN: 292

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1

Other (OTH) AF: 0.00 AC: 0 AN: 3

GnomAD4 genome AF: 0.0142 AC: 1589 AN: 111918 Hom.: 14 Cov.: 22 AF XY: 0.0119 AC XY: 408 AN XY: 34156

African (AFR) AF: 0.00395 AC: 122 AN: 30907

American (AMR) AF: 0.0147 AC: 154 AN: 10499

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2648

East Asian (EAS) AF: 0.0109 AC: 39 AN: 3591

South Asian (SAS) AF: 0.00367 AC: 10 AN: 2724

European-Finnish (FIN) AF: 0.0161 AC: 97 AN: 6035

Middle Eastern (MID) AF: 0.0137 AC: 3 AN: 219

European-Non Finnish (NFE) AF: 0.0215 AC: 1140 AN: 53086

Other (OTH) AF: 0.0111 AC: 17 AN: 1528

Alfa AF: 0.00446 Hom.: 18

Bravo AF: 0.0148

Asia WGS AF: 0.00519 AC: 13 AN: 2516

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Dilated cardiomyopathy 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs202154420; hg19: chrX-31137798;