rs771242421

Variant names:

• chrX-31120327-T-TAACA
• rs771242421
• NM_004006.3:c.*1588_*1591dupTGTT

Your query was ambiguous. Multiple possible variants found:

• chrX-31120327-T-TAACA
• chrX-31120327-T-TAAC

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.*1588_*1591dupTGTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 109,700 control chromosomes in the GnomAD database, including 2 homozygotes. There are 77 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., 77 hem., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD NM_004006.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• 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: 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

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 = 0.00237 (260/109700) while in subpopulation NFE AF = 0.00361 (190/52680). AF 95% confidence interval is 0.00319. There are 2 homozygotes in GnomAd4. There are 77 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 260 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.*1588_*1591dupTGTT		3_prime_UTR	Exon 79 of 79	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.*1588_*1591dupTGTT		3_prime_UTR	Exon 79 of 79	NP_004000.1	P11532
	DMD	NM_000109.4		c.*1588_*1591dupTGTT		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.*1588_*1591dupTGTT		3_prime_UTR	Exon 79 of 79	ENSP00000354923.3	P11532-1
	DMD	ENST00000378723.7	TSL:1	c.*1502_*1505dupTGTT		3_prime_UTR	Exon 17 of 17	ENSP00000367997.3	P11532-6
	DMD	ENST00000378677.6	TSL:5	c.*1588_*1591dupTGTT		3_prime_UTR	Exon 79 of 79	ENSP00000367948.2	P11532-11

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 260 AN: 109652 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00290

Gnomad ASJ AF: 0.00874

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00116

Gnomad FIN AF: 0.000169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00361

Gnomad OTH AF: 0.00202

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 287 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 115

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: 0.00 AC: 0 AN: 282

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

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

GnomAD4 genome AF: 0.00237 AC: 260 AN: 109700 Hom.: 2 Cov.: 22 AF XY: 0.00240 AC XY: 77 AN XY: 32048

African (AFR) AF: 0.000338 AC: 10 AN: 29555

American (AMR) AF: 0.00290 AC: 30 AN: 10355

Ashkenazi Jewish (ASJ) AF: 0.00874 AC: 23 AN: 2633

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00116 AC: 3 AN: 2578

European-Finnish (FIN) AF: 0.000169 AC: 1 AN: 5930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00361 AC: 190 AN: 52680

Other (OTH) AF: 0.00200 AC: 3 AN: 1502

Alfa AF: 0.00178 Hom.: 11

Bravo AF: 0.00250

ClinVar

ClinVar submissions as Germline

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		2.0
Mutation Taster		=99/1	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs771242421; hg19: chrX-31138444;