X-33211281-C-A

Variant names:

• chrX-33211281-C-A
• rs398123923
• NM_004006.3:c.31+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_004006.3(DMD):​c.31+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000913 in 1,095,773 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 (★★). ClinVar reports functional evidence for this variant: "SCV000235850: RNA studies demonstrate a damaging effect of this variant in dystrophin levels (PMID:17826093); SCV002607788: Trancscriptional studies from patients with this mutation indicated absence of transcript from the muscle promotor in skeletal and heart muscle, while upregulation of alternate promoters appeared to result in production of other DMD isoforms in skeletal muscle, albeit at reduced levels (Milasin J et al. Hum. Mol. Genet., 1996 Jan;5:73-9; Neri M et al. Neuromuscul. Disord., 2007 Dec;17:913-8).".

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 5.75
• 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: 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000235850: RNA studies demonstrate a damaging effect of this variant in dystrophin levels (PMID: 17826093); SCV002607788: Trancscriptional studies from patients with this mutation indicated absence of transcript from the muscle promotor in skeletal and heart muscle, while upregulation of alternate promoters appeared to result in production of other DMD isoforms in skeletal muscle, albeit at reduced levels (Milasin J et al. Hum. Mol. Genet., 1996 Jan;5:73-9; Neri M et al. Neuromuscul. Disord., 2007 Dec;17:913-8).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-33211281-C-A is Pathogenic according to our data. Variant chrX-33211281-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 94554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.31+1G>T		splice_donor intron	N/A	NP_003997.2	P11532-1
	DMD	NM_000109.4		c.7+127978G>T		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.31+1G>T		splice_donor intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000288447.9	TSL:1	c.7+127978G>T		intron	N/A	ENSP00000288447.4	Q4G0X0
	DMD	ENST00000682071.1		c.-501+1G>T		splice_donor intron	N/A	ENSP00000508133.1	A0A804HKZ5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095773 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 361653

African (AFR) AF: 0.00 AC: 0 AN: 26356

American (AMR) AF: 0.00 AC: 0 AN: 35030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19339

East Asian (EAS) AF: 0.00 AC: 0 AN: 30130

South Asian (SAS) AF: 0.00 AC: 0 AN: 53826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840609

Other (OTH) AF: 0.00 AC: 0 AN: 45968

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Dilated cardiomyopathy 3B (4)
3	-	-	not provided (3)
1	-	-	Becker muscular dystrophy (1)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Duchenne muscular dystrophy (1)
1	-	-	Duchenne muscular dystrophy;C0878544:Cardiomyopathy;C0917713:Becker muscular dystrophy;na:Dystrophin deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	32
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		5.8
GERP RS		6.0
PromoterAI		-0.19	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

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

Other links and lift over

dbSNP: rs398123923; hg19: chrX-33229398;