rs1556962217

Variant names:

• chrX-31875185-T-A
• rs1556962217
• NM_004006.3:c.7098+3A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004006.3(DMD):​c.7098+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000919 in 1,088,283 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: DMD NM_004006.3 splice_region, intron
• Scores: Splicing: ADA: 0.9889
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.934
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.7098+3A>T		splice_region intron	N/A	NP_003997.2	P11532-1
	DMD	NM_004009.3		c.7086+3A>T		splice_region intron	N/A	NP_004000.1	P11532
	DMD	NM_000109.4		c.7074+3A>T		splice_region 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.7098+3A>T		splice_region intron	N/A	ENSP00000354923.3	P11532-1
	DMD	ENST00000378677.6	TSL:5	c.7086+3A>T		splice_region intron	N/A	ENSP00000367948.2	P11532-11
	DMD	ENST00000619831.5	TSL:5	c.3066+3A>T		splice_region intron	N/A	ENSP00000479270.2	A0A087WV90

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.19e-7 AC: 1 AN: 1088283 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 355467

African (AFR) AF: 0.0000383 AC: 1 AN: 26101

American (AMR) AF: 0.00 AC: 0 AN: 33984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19096

East Asian (EAS) AF: 0.00 AC: 0 AN: 30073

South Asian (SAS) AF: 0.00 AC: 0 AN: 52380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40255

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4045

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 836695

Other (OTH) AF: 0.00 AC: 0 AN: 45654

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Duchenne muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Benign	0.74
PhyloP100		0.93
PromoterAI		-0.10	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1556962217; hg19: chrX-31893302;