chr6-7565494-A-T

Position:

chr6-7565494-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_004415.4(DSP):c.913A>T(p.Ile305Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,613,890 control chromosomes in the GnomAD database, including 1,250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 93 hom., cov: 31)

Exomes 𝑓: 0.038 ( 1157 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23

Conservation

PhyloP100: 9.20

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:

DSP (HGNC:):

DSP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0029249191).

BP6

Variant 6-7565494-A-T is Benign according to our data. Variant chr6-7565494-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 36026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7565494-A-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0269 (4099/152148) while in subpopulation NFE AF= 0.0408 (2771/67978). AF 95% confidence interval is 0.0395. There are 93 homozygotes in gnomad4. There are 1921 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 93 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.913A>T	p.Ile305Phe	missense_variant	7/24	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 linkuse as main transcript	c.913A>T	p.Ile305Phe	missense_variant	7/24		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 linkuse as main transcript	c.913A>T	p.Ile305Phe	missense_variant	7/24		NP_001008844.1	P15924-2B4DKX6Q4LE79
DSP	NM_001406591.1 linkuse as main transcript	c.913A>T	p.Ile305Phe	missense_variant	7/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.913A>T	p.Ile305Phe	missense_variant	7/24	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.0270

AC:

4098

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00604

Gnomad AMI

AF:

0.167

Gnomad AMR

AF:

0.0190

Gnomad ASJ

AF:

0.0467

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0384

Gnomad FIN

AF:

0.0212

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0408

Gnomad OTH

AF:

0.0210

GnomAD3 exomes

AF:

0.0296

AC:

7436

AN:

251262

Hom.:

151

AF XY:

0.0315

AC XY:

4272

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00652

Gnomad AMR exome

AF:

0.0153

Gnomad ASJ exome

AF:

0.0447

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0363

Gnomad FIN exome

AF:

0.0245

Gnomad NFE exome

AF:

0.0396

Gnomad OTH exome

AF:

0.0342

GnomAD4 exome

AF:

0.0376

AC:

54918

AN:

1461742

Hom.:

1157

Cov.:

AF XY:

0.0378

AC XY:

27494

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00568

Gnomad4 AMR exome

AF:

0.0157

Gnomad4 ASJ exome

AF:

0.0453

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0373

Gnomad4 FIN exome

AF:

0.0248

Gnomad4 NFE exome

AF:

0.0414

Gnomad4 OTH exome

AF:

0.0341

GnomAD4 genome

AF:

0.0269

AC:

4099

AN:

152148

Hom.:

Cov.:

AF XY:

0.0258

AC XY:

1921

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00602

Gnomad4 AMR

AF:

0.0190

Gnomad4 ASJ

AF:

0.0467

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0393

Gnomad4 FIN

AF:

0.0212

Gnomad4 NFE

AF:

0.0408

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.0354

Hom.:

Bravo

AF:

0.0256

TwinsUK

AF:

0.0445

AC:

165

ALSPAC

AF:

0.0464

AC:

179

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0419

AC:

360

ExAC

AF:

0.0299

AC:

3632

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.0417

EpiControl

AF:

0.0411

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:23

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:10

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2011	Ile305Phe in exon 7 of DSP: This variant is classified as benign based on its hi gh frequency in the general population (rs17604693, MAF >3%). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiomyopathy

Benign:4

Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 07, 2018	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 03, 2019	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	This variant is associated with the following publications: (PMID: 33232181, 27153395, 19863551, 25445213) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

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

Feb 01, 2024

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Feb 19, 2015

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Woolly hair-skin fragility syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Arrhythmogenic right ventricular dysplasia 8

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2015

This alteration is classified as 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

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

MetaRNN

Benign

0.0029

T;T

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.031

D;T

Polyphen

1.0

D;.

Vest4

0.29

MPC

1.0

ClinPred

0.027

GERP RS

5.5

Varity_R

0.40

gMVP

0.72

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