rs606231377

Variant names:

• chr6-7541915-C-CA
• rs17133512
• NM_004415.4:c.1dupA

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BA1

The NM_004415.4(DSP):​c.1dupA​(p.Met1fs) variant causes a frameshift, start lost 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 frameshift, start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:15
• Conservation: PhyloP100: 3.29

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

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 87 pathogenic variants in the truncated region.
• 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: {Uncertain_significance=1, Benign=12}.
• 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 rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1dupA	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 24	ENST00000379802.8	NP_004406.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1dupA	p.Met1fs	frameshift_variant, start_lost	Exon 1 of 24	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26256 AN: 152080 Hom.: 2450 Cov.: 30

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

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.: 32 AF XY: 0.144 AC XY: 104253 AN XY: 724520

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.: 30 AF XY: 0.175 AC XY: 13040 AN XY: 74410

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:1 Benign:15

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:9

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, 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	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Feb 17, 2025	- -

Cardiomyopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -

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

- -

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

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

Other links and lift over

dbSNP: rs17133512; hg19: chr6-7542148;