rs1060500614

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_004415.4(DSP):​c.2680A>T​(p.Asn894Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

DSP
NM_004415.4 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.33721992).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSPNM_004415.4 linkuse as main transcriptc.2680A>T p.Asn894Tyr missense_variant 19/24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkuse as main transcriptc.2680A>T p.Asn894Tyr missense_variant 19/24 NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkuse as main transcriptc.2680A>T p.Asn894Tyr missense_variant 19/24 NP_001008844.1 P15924-2B4DKX6Q4LE79

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.2680A>T p.Asn894Tyr missense_variant 19/241 NM_004415.4 ENSP00000369129.3 P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.2680A>T p.Asn894Tyr missense_variant 19/241 ENSP00000396591.2 P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.2680A>T p.Asn894Tyr missense_variant 19/24 ENSP00000518230.1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 21, 2016This sequence change replaces asparagine with tyrosine at codon 894 of the DSP protein (p.Asn894Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DSP-related disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.059
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
T;.
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.34
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;N
PrimateAI
Uncertain
0.62
T
PROVEAN
Uncertain
-2.6
D;N
REVEL
Benign
0.12
Sift
Uncertain
0.0080
D;D
Sift4G
Uncertain
0.022
D;T
Polyphen
0.85
P;.
Vest4
0.43
MutPred
0.40
Loss of MoRF binding (P = 0.118);Loss of MoRF binding (P = 0.118);
MVP
0.46
MPC
0.32
ClinPred
0.83
D
GERP RS
6.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.11
gMVP
0.32

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: rs1060500614; hg19: chr6-7576576; API