rs727504738

chr6-7559293-GCC-GAGCTCGAGTCCCTCG

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_004415.4(DSP):c.491_492delinsAGCTCGAGTCCCTCG(p.Ala164GlufsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A164A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.45

Genes affected

DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-7559294-CC-AGCTCGAGTCCCTCG is Pathogenic according to our data. Variant chr6-7559294-CC-AGCTCGAGTCCCTCG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179249.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.491_492delinsAGCTCGAGTCCCTCG	p.Ala164GlufsTer23	frameshift_variant	4/24	ENST00000379802.8
DSP	NM_001008844.3	c.491_492delinsAGCTCGAGTCCCTCG	p.Ala164GlufsTer23	frameshift_variant	4/24
DSP	NM_001319034.2	c.491_492delinsAGCTCGAGTCCCTCG	p.Ala164GlufsTer23	frameshift_variant	4/24
DSP	NM_001406591.1	c.491_492delinsAGCTCGAGTCCCTCG	p.Ala164GlufsTer23	frameshift_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.491_492delinsAGCTCGAGTCCCTCG	p.Ala164GlufsTer23	frameshift_variant	4/24	1	NM_004415.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2013

The Ala164fs variant in DSP has not been reported in individuals with cardiomyop athy or in large population studies. This frameshift variant is predicted to alt er the protein?s amino acid sequence beginning at position 164 and lead to a pre mature termination codon 23 amino acids downstream. This alteration is then pred icted to lead to a truncated or absent protein. Frameshift and nonsense variants in DSP are common in patients with ARVC (http://arvcdatabase.info/), but recent evidence supports that they can also cause DCM (Elliott 2010, Garcia-Pavia 2011 ). In summary, this variant is likely to be pathogenic, though additional studie s are required to fully establish its clinical significance. -

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: rs727504738; hg19: chr6-7559527;