X-32287704-G-T

Variant names:

• chrX-32287704-G-T
• rs730880074
• NM_004006.3:c.6118-3C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000357033.9(DMD):​c.6118-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: DMD ENST00000357033.9 splice_region, intron
• Scores: Splicing: ADA: 0.9755
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.26
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000357033.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	NM_004006.3	MANE Select	c.6118-3C>A		splice_region intron	N/A	NP_003997.2
	DMD	NM_004009.3		c.6106-3C>A		splice_region intron	N/A	NP_004000.1
	DMD	NM_000109.4		c.6094-3C>A		splice_region intron	N/A	NP_000100.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DMD	ENST00000357033.9	TSL:1 MANE Select	c.6118-3C>A		splice_region intron	N/A	ENSP00000354923.3
	DMD	ENST00000378677.6	TSL:5	c.6106-3C>A		splice_region intron	N/A	ENSP00000367948.2
	DMD	ENST00000619831.5	TSL:5	c.2086-3C>A		splice_region intron	N/A	ENSP00000479270.2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1047440 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 325256

African (AFR) AF: 0.00 AC: 0 AN: 24586

American (AMR) AF: 0.00 AC: 0 AN: 32902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18717

East Asian (EAS) AF: 0.00 AC: 0 AN: 28309

South Asian (SAS) AF: 0.00 AC: 0 AN: 48420

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3959

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 807780

Other (OTH) AF: 0.00 AC: 0 AN: 43997

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.71
PhyloP100		3.3
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.42		Position offset: -3

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

Other links and lift over

dbSNP: rs730880074; hg19: chrX-32305821;