rs606231377

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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

Our verdict: Likely_benign. The variant received -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 492 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

GnomAD2 exomes AF: 0.167 AC: 38677 AN: 231420 AF XY: 0.161

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 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 AC: 7426 AN: 33394

Gnomad4 AMR exome AF: 0.238 AC: 10553 AN: 44360

Gnomad4 ASJ exome AF: 0.104 AC: 2711 AN: 26046

Gnomad4 EAS exome AF: 0.302 AC: 11958 AN: 39574

Gnomad4 SAS exome AF: 0.125 AC: 10692 AN: 85634

Gnomad4 FIN exome AF: 0.171 AC: 8810 AN: 51424

Gnomad4 NFE exome AF: 0.135 AC: 150468 AN: 1110760

Gnomad4 Remaining exome AF: 0.148 AC: 8915 AN: 60168

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 AC: 0.214623 AN: 0.214623

Gnomad4 AMR AF: 0.217 AC: 0.216573 AN: 0.216573

Gnomad4 ASJ AF: 0.109 AC: 0.109222 AN: 0.109222

Gnomad4 EAS AF: 0.269 AC: 0.269171 AN: 0.269171

Gnomad4 SAS AF: 0.127 AC: 0.127435 AN: 0.127435

Gnomad4 FIN AF: 0.165 AC: 0.16494 AN: 0.16494

Gnomad4 NFE AF: 0.138 AC: 0.138388 AN: 0.138388

Gnomad4 OTH AF: 0.157 AC: 0.157048 AN: 0.157048

Alfa AF: 0.127 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

May 03, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 20, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 17, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cardiomyopathy Benign:2

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:1

Sep 26, 2016

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Arrhythmogenic right ventricular cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Woolly hair-skin fragility syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 22, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
Mutation Taster		=99/1	polymorphism (auto)

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; COSMIC: COSV65791211; COSMIC: COSV65791211;