rs727504909

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4

The NM_004415.4(DSP):​c.8576_8577del​(p.Ser2859LeufsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

DSP
NM_004415.4 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.40
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 2963 codons.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSPNM_004415.4 linkuse as main transcriptc.8576_8577del p.Ser2859LeufsTer6 frameshift_variant 24/24 ENST00000379802.8 NP_004406.2
DSPNM_001008844.3 linkuse as main transcriptc.6779_6780del p.Ser2260LeufsTer6 frameshift_variant 24/24 NP_001008844.1
DSPNM_001319034.2 linkuse as main transcriptc.7247_7248del p.Ser2416LeufsTer6 frameshift_variant 24/24 NP_001305963.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.8576_8577del p.Ser2859LeufsTer6 frameshift_variant 24/241 NM_004415.4 ENSP00000369129 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.6779_6780del p.Ser2260LeufsTer6 frameshift_variant 24/241 ENSP00000396591 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.7247_7248del p.Ser2416LeufsTer6 frameshift_variant 24/24 ENSP00000518230 A2

Frequencies

GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 17, 2014Variant classified as Uncertain Significance - Favor Pathogenic. The Ser2859fs v ariant in DSP has not been reported in individuals with cardiomyopathy or in lar ge population studies. This frameshift variant is predicted to alter the protein ?s amino acid sequence beginning at position 2859 and leads to a premature termi nation codon 6 amino acids downstream, resulting in a loss of the last 6 amino a cids of the DSP protein and may not. It is unclear if this variant would undergo nonsense mediated decay and cause a loss of function variant. However, homozygo us variants that truncate the tail of the DSP protein have been reported in indi viduals with Carvajal syndrome and/or acantholytic epidermolysis bullosa (Cheong 2005, Jonkman 2005, Rasmussen 2013). Although this data supports that the Ser28 59fs variant may be pathogenic in homozygous configuration, additional studies a re needed to fully assess its clinical significance. -
Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthApr 15, 2023- -

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: rs727504909; hg19: chr6-7586068; API