chr6-7585562-C-A

Position:

chr6-7585562-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004415.4(DSP):c.8300C>A(p.Thr2767Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,108 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2767I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0064 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 5 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.556

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056839883).

BP6

Variant 6-7585562-C-A is Benign according to our data. Variant chr6-7585562-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 44963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7585562-C-A is described in Lovd as [Benign]. Variant chr6-7585562-C-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0064 (974/152232) while in subpopulation AFR AF= 0.0227 (941/41534). AF 95% confidence interval is 0.0215. There are 9 homozygotes in gnomad4. There are 425 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSP	NM_004415.4 linkuse as main transcript	c.8300C>A	p.Thr2767Asn	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2 linkuse as main transcript	c.6971C>A	p.Thr2324Asn	missense_variant	24/24
DSP	NM_001008844.3 linkuse as main transcript	c.6503C>A	p.Thr2168Asn	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.8300C>A	p.Thr2767Asn	missense_variant	24/24	1	NM_004415.4	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.6503C>A	p.Thr2168Asn	missense_variant	24/24	1		A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.6971C>A	p.Thr2324Asn	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes

AF:

0.00641

AC:

975

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

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:

0.0000147

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00171

AC:

429

AN:

251380

Hom.:

AF XY:

0.00116

AC XY:

158

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.000839

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:

0.0000176

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000642

AC:

939

AN:

1461876

Hom.:

Cov.:

AF XY:

0.000579

AC XY:

421

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0245

Gnomad4 AMR exome

AF:

0.000805

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00640

AC:

974

AN:

152232

Hom.:

Cov.:

AF XY:

0.00571

AC XY:

425

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.0227

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.000862

Hom.:

Bravo

AF:

0.00681

ESP6500AA

AF:

0.0227

AC:

100

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00212

AC:

257

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 19, 2012	p.Thr2767Asn in Exon 24 of DSP: This variant is not expected to have clinical si gnificance because it has been identified in 2.3% (87/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs34884895). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cardiomyopathy

Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 09, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 22, 2018	- -
Benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	DSP: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 22, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Woolly hair-skin fragility syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy;C1135191:Systolic heart failure

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jun 03, 2019

- -

Epidermolysis bullosa simplex due to plakophilin deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

T;.

Eigen

Benign

0.060

Eigen_PC

Benign

-0.014

FATHMM_MKL

Benign

0.63

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

0.68

N;N

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.8

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.90

P;.

Vest4

0.29

MVP

0.70

MPC

0.61

ClinPred

0.030

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.44

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

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