rs17133512

chr6-7541915-C-CA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BA1

The NM_004415.4(DSP):c.1dup(p.Met1AsnfsTer?) variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,609,250 control chromosomes in the GnomAD database, including 19,165 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.17 ( 2453 hom., cov: 30)

Exomes 𝑓: 0.15 ( 16712 hom. )

Consequence

DSP
NM_004415.4 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:15

Conservation

PhyloP100: 3.29

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-AS1 (HGNC:56039): (DSP antisense RNA 1)

DSP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 6-7541915-C-CA is Benign according to our data. Variant chr6-7541915-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36015.We mark this variant Likely_benign, oryginal submissions are: {Benign=12, Uncertain_significance=1}.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4 linkuse as main transcript	c.1dup	p.Met1AsnfsTer?	5_prime_UTR_variant	1/24	ENST00000379802.8
DSP-AS1	NR_183331.1 linkuse as main transcript	n.39-863_39-862insT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.1dup	p.Met1AsnfsTer?	5_prime_UTR_variant	1/24	1	NM_004415.4	P2	P15924-1
DSP-AS1	ENST00000690863.2 linkuse as main transcript	n.344+855_344+856insT		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26256

AN:

152080

Hom.:

2450

Cov.:

show subpopulations

Gnomad AFR

AF:

0.215

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.216

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.127

Gnomad FIN

AF:

0.165

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.138

Gnomad OTH

AF:

0.156

GnomAD3 exomes

AF:

0.167

AC:

38677

AN:

231420

Hom.:

3569

AF XY:

0.161

AC XY:

20455

AN XY:

127368

show subpopulations

Gnomad AFR exome

AF:

0.217

Gnomad AMR exome

AF:

0.244

Gnomad ASJ exome

AF:

0.102

Gnomad EAS exome

AF:

0.262

Gnomad SAS exome

AF:

0.126

Gnomad FIN exome

AF:

0.174

Gnomad NFE exome

AF:

0.137

Gnomad OTH exome

AF:

0.149

GnomAD4 exome

AF:

0.146

AC:

212018

AN:

1457052

Hom.:

16712

Cov.:

AF XY:

0.144

AC XY:

104253

AN XY:

724520

show subpopulations

Gnomad4 AFR exome

AF:

0.222

Gnomad4 AMR exome

AF:

0.238

Gnomad4 ASJ exome

AF:

0.104

Gnomad4 EAS exome

AF:

0.302

Gnomad4 SAS exome

AF:

0.125

Gnomad4 FIN exome

AF:

0.171

Gnomad4 NFE exome

AF:

0.135

Gnomad4 OTH exome

AF:

0.148

GnomAD4 genome

AF:

0.173

AC:

26267

AN:

152198

Hom.:

2453

Cov.:

AF XY:

0.175

AC XY:

13040

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.215

Gnomad4 AMR

AF:

0.217

Gnomad4 ASJ

AF:

0.109

Gnomad4 EAS

AF:

0.269

Gnomad4 SAS

AF:

0.127

Gnomad4 FIN

AF:

0.165

Gnomad4 NFE

AF:

0.138

Gnomad4 OTH

AF:

0.157

Alfa

AF:

0.143

Hom.:

1031

Bravo

AF:

0.177

Asia WGS

AF:

0.205

AC:

711

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:8

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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 24, 2019	Variant summary: DSP c.1dupA is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.17 in 231420 control chromosomes in the gnomAD database, including 3569 homozygotes. The observed variant frequency is approximately 6685.078 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.1dupA has been reported in the literature in individuals affected with Cardiomyopathy. These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2017	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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 03, 2010	The variant has been reported in dbSNP without frequency information (rs17133512 ). Classified as benign based on high allele frequency (0.162, n=290 chromosomes ) in ARVC probands tested at the LMM. In addition, the fraction of probands carr ying the -1_1insA variant matches the expected detection rate for ARVC (~50%), f urther supporting a benign role. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cardiomyopathy

Benign:2

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 09, 2018	- -

Arrhythmogenic right ventricular dysplasia 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Sep 26, 2016

- -

Arrhythmogenic right ventricular cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Lethal acantholytic epidermolysis bullosa

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Woolly hair-skin fragility syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2015

Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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