rs794728138

Variant names:

• chr6-7565513-CCTT-C
• rs794728138
• NM_004415.4:c.935_937delTCT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PM4_Supporting

The NM_004415.4(DSP):​c.935_937delTCT​(p.Phe312del) variant causes a disruptive inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DSP NM_004415.4 disruptive_inframe_deletion, splice_region
• 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 5 ACMG points.

• PM1: In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004415.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.935_937delTCT	p.Phe312del	disruptive_inframe_deletion, splice_region_variant	Exon 7 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.935_937delTCT	p.Phe312del	disruptive_inframe_deletion, splice_region_variant	Exon 7 of 24		NP_001305963.1
DSP	NM_001008844.3	c.935_937delTCT	p.Phe312del	disruptive_inframe_deletion, splice_region_variant	Exon 7 of 24		NP_001008844.1
DSP	NM_001406591.1	c.935_937delTCT	p.Phe312del	disruptive_inframe_deletion, splice_region_variant	Exon 7 of 11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.935_937delTCT	p.Phe312del	disruptive_inframe_deletion, splice_region_variant	Exon 7 of 24	1	NM_004415.4	ENSP00000369129.3

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

-

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Aug 27, 2013

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 07, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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 is not present in population databases (ExAC no frequency). 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. -

Cardiovascular phenotype Uncertain:1

Aug 06, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;