rs794728138

Positions:

• chr6-7565513-CCTT-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The ENST00000379802.8(DSP):​c.935_937del​(p.Phe312del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP ENST00000379802.8 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000379802.8. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.935_937del	p.Phe312del	inframe_deletion	7/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3	c.935_937del	p.Phe312del	inframe_deletion	7/24		NP_001008844.1
DSP	NM_001319034.2	c.935_937del	p.Phe312del	inframe_deletion	7/24		NP_001305963.1
DSP	NM_001406591.1	c.935_937del	p.Phe312del	inframe_deletion	7/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.935_937del	p.Phe312del	inframe_deletion	7/24	1	NM_004415.4	ENSP00000369129	P2

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2013	c.935_937delTCT: p.Phe312del (F312del) in exon 7 of the DSP gene (NM_004415.2). The normal sequence with the bases that are deleted in braces is: GCCT{TCT}CCgt.The c.935_937delTCT variant in the DSP gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The c.935_937delTCT variant results in an in-frame deletion of a Phenylalanine at codon 312 in the DSP gene. The c.935_937delTCT variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. One in-frame deletion has been reported in association with ARVC as well as a missense mutation in a neighboring codon (Ser299Arg). With the clinical and molecular information available at this time, we cannot definitively determine if c.935_937delTCT is a disease-causing mutation or a rare benign variant. The variant is found in ARVC panel(s). -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 07, 2019

This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DSP-related disease. ClinVar contains an entry for this variant (Variation ID: 199917). This variant, c.935_937delTCT, results in the deletion of 1 amino acid of the DSP protein (p.Phe312del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2019

The c.935_937delTCT variant (also known as p.F312del) is located in coding exon 7 of the DSP gene. This variant results from an in-frame TCT deletion at nucleotide positions 935 to 937. This results in the in-frame deletion of a phenylalanine residue at codon 312. This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs794728138; hg19: chr6-7565746;