X-32454660-A-T

Variant names:

• chrX-32454660-A-T
• rs146071084
• NM_004006.3:c.3603+2T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_004006.3(DMD):​c.3603+2T>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 0 hem., cov: 14)
  • Exomes 𝑓: 0.000012 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD NM_004006.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.30
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0154639175 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant X-32454660-A-T is Pathogenic according to our data. Variant chrX-32454660-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 94598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DMD	NM_004006.3	c.3603+2T>A		splice_donor_variant, intron_variant	Intron 26 of 78	ENST00000357033.9	NP_003997.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DMD	ENST00000357033.9	c.3603+2T>A		splice_donor_variant, intron_variant	Intron 26 of 78	1	NM_004006.3	ENSP00000354923.3

Frequencies

GnomAD3 genomes AF: 0.000229 AC: 13 AN: 56823 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.0000481

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000408

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000810

Gnomad FIN AF: 0.000492

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000335

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000221 AC: 3 AN: 135786 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000471

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000122 AC: 10 AN: 820013 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 237563

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22106

American (AMR) AF: 0.0000417 AC: 1 AN: 23977

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15432

East Asian (EAS) AF: 0.00 AC: 0 AN: 25180

South Asian (SAS) AF: 0.00 AC: 0 AN: 36270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28410

Middle Eastern (MID) AF: 0.000347 AC: 1 AN: 2880

European-Non Finnish (NFE) AF: 0.0000127 AC: 8 AN: 630269

Other (OTH) AF: 0.00 AC: 0 AN: 35489

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000229 AC: 13 AN: 56851 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 14909

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000480 AC: 1 AN: 20824

American (AMR) AF: 0.000407 AC: 2 AN: 4912

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1353

East Asian (EAS) AF: 0.00 AC: 0 AN: 1496

South Asian (SAS) AF: 0.000815 AC: 1 AN: 1227

European-Finnish (FIN) AF: 0.000492 AC: 1 AN: 2032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 87

European-Non Finnish (NFE) AF: 0.000335 AC: 8 AN: 23847

Other (OTH) AF: 0.00 AC: 0 AN: 742

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000209 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Aug 22, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Duchenne muscular dystrophy Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	0.99
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.3
GERP RS		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 2

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

Other links and lift over

dbSNP: rs146071084; hg19: chrX-32472777; COSMIC: COSV63747121;