rs794728151

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM4PP3BP6_Very_Strong

The NM_004415.4(DSP):c.8529_8540del(p.Ser2843_Arg2846del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000702 in 1,609,842 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2843S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

DSP
NM_004415.4 inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:4

Conservation

PhyloP100: 9.75

Variant links:

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]

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_004415.4.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 6-7585788-CAGTGGGTCCCGG-C is Benign according to our data. Variant chr6-7585788-CAGTGGGTCCCGG-C is described in ClinVar as [Likely_benign]. Clinvar id is 199930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSP	NM_004415.4 linkuse as main transcript	c.8529_8540del	p.Ser2843_Arg2846del	inframe_deletion	24/24	ENST00000379802.8
DSP	NM_001008844.3 linkuse as main transcript	c.6732_6743del	p.Ser2244_Arg2247del	inframe_deletion	24/24
DSP	NM_001319034.2 linkuse as main transcript	c.7200_7211del	p.Ser2400_Arg2403del	inframe_deletion	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.8529_8540del	p.Ser2843_Arg2846del	inframe_deletion	24/24	1	NM_004415.4	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.6732_6743del	p.Ser2244_Arg2247del	inframe_deletion	24/24	1		A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.7200_7211del	p.Ser2400_Arg2403del	inframe_deletion	24/24			A2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000396

AC:

AN:

245192

Hom.:

AF XY:

0.000249

AC XY:

AN XY:

132794

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000748

AC:

109

AN:

1457538

Hom.:

AF XY:

0.0000607

AC XY:

AN XY:

725024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00250

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000128

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Mar 27, 2014

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Given that the variant is novel, and the type of variant we consider this variant a varian of uncertain significance. Variants in DSP have been associated with cardiomyopathy, primarily ARVC but also some cases of DCM (which may be left-sided ARVC). To our knowledge, the variant is novel. This is an in-frame deletion of four amino acids. Only one in-frame deletion has been reported before in associated with ARVC in HGMD. A neighboring in-frame deletion of the same size (p.Ser2843_Arg2846del) was observed in 1 of 427 "ostensibly healthy" controls studied by Kapplinger et al (2011) and a patient with DCM in the LMM cohort who also carried variants in MYH6, TTN, ABCC9, DSG2, and MYL3 (Pugh et al 2014). This variant is not listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of July 28th, 2014). However, this is not a reliable dataset for multi-nucleotide insertions or deletions. There variant is not listed in dbSNP (as of July 29th, 2014). -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 09, 2023

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 29, 2018

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2020

This variant is associated with the following publications: (PMID: 21636032, 27532257, 24503780) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over