rs606231377

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1BP6BA1

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

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

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
DSPNM_004415.4 linkc.1dupA p.Met1fs frameshift_variant, start_lost Exon 1 of 24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkc.1dupA p.Met1fs frameshift_variant, start_lost Exon 1 of 24 1 NM_004415.4 ENSP00000369129.3 P15924-1

Frequencies

GnomAD3 genomes
AF:
0.173
AC:
26256
AN:
152080
Hom.:
2450
Cov.:
30
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.:
32
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.:
30
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: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. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
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, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
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

- -

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. -

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

- -

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

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.

Other links and lift over

dbSNP: rs17133512; hg19: chr6-7542148; API