Variant rs727504704 details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004415.4(DSP):c.8487_8498del(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 0.0000422 in 1,610,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

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

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

DSP
NM_004415.4 inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 8.12

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 6-7585746-CTCCCGCTCGGGA-C is Benign according to our data. Variant chr6-7585746-CTCCCGCTCGGGA-C is described in ClinVar as [Likely_benign]. Clinvar id is 179202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7585746-CTCCCGCTCGGGA-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DSP	NM_004415.4 linkuse as main transcript	c.8487_8498del	p.Ser2843_Arg2846del	inframe_deletion	24/24	ENST00000379802.8	NP_004406.2
DSP	NM_001008844.3 linkuse as main transcript	c.6690_6701del	p.Ser2244_Arg2247del	inframe_deletion	24/24		NP_001008844.1
DSP	NM_001319034.2 linkuse as main transcript	c.7158_7169del	p.Ser2400_Arg2403del	inframe_deletion	24/24		NP_001305963.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.8487_8498del	p.Ser2843_Arg2846del	inframe_deletion	24/24	1	NM_004415.4	ENSP00000369129	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.6690_6701del	p.Ser2244_Arg2247del	inframe_deletion	24/24	1		ENSP00000396591	A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.7158_7169del	p.Ser2400_Arg2403del	inframe_deletion	24/24			ENSP00000518230	A2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000485

AC:

AN:

247200

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000439

AC:

AN:

1458042

Hom.:

AF XY:

0.0000414

AC XY:

AN XY:

725088

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000577

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000169

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2021	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 20, 2013

Ser2843_Arg2846del in exon 24 of DSP: This variant has not been reported in ind ividuals with cardiomyopathy or in large population studies and is not expected to have clinical significance. It was previously identified in 0.7% (61/8254) of European American chromosomes by the NHLBI Exome Sequencing Project; however, t hat data is no longer available (http://evs.gs.washington.edu/EVS/). This varian t was not identified in a cohort of 350 chromosomes of mixed race with ARVC; how ever, it was idenitified in 1/854 healthy, race-matched control chromosomes (Kap plinger 2011). This in-frame deletion of four amino acids occurs within a sectio n of repeating amino acids, which can result from several different DNA deletion s, and is present in at least three mammals (dolphin, opossum, and platypus) and other evolutionarily distant species. Although this data supports that the Ser2 843_Arg2846del variant may be benign, additional studies are needed to fully ass ess its clinical significance. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2023

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 04, 2020

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2018

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. -

DSP-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 22, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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