rs1064792968

chrX-31223122-CTGAAAAGAGGGAAAACAAAGAGCATT-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PP5_Moderate

The NM_004006.3(DMD):c.9287-27_9287-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: DMD NM_004006.3 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0066919876 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant X-31223122-CTGAAAAGAGGGAAAACAAAGAGCATT-C is Pathogenic according to our data. Variant chrX-31223122-CTGAAAAGAGGGAAAACAAAGAGCATT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 409934.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DMD	NM_004006.3	c.9287-27_9287-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000357033.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DMD	ENST00000357033.9	c.9287-27_9287-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004006.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duchenne muscular dystrophy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 07, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of Duchenne muscular dystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 409934). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 63 of the DMD gene. It does not directly change the encoded amino acid sequence of the DMD protein, but it affects a nucleotide within the consensus splice site of the intron. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064792968; hg19: chrX-31241239;