rs1554106853

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000379802.8(DSP):ā€‹c.1382T>Cā€‹(p.Ile461Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. I461I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

DSP
ENST00000379802.8 missense

Scores

5
11
3

Clinical Significance

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

Conservation

PhyloP100: 8.02
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 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DSPNM_004415.4 linkuse as main transcriptc.1382T>C p.Ile461Thr missense_variant 11/24 ENST00000379802.8 NP_004406.2
DSPNM_001319034.2 linkuse as main transcriptc.1382T>C p.Ile461Thr missense_variant 11/24 NP_001305963.1
DSPNM_001008844.3 linkuse as main transcriptc.1382T>C p.Ile461Thr missense_variant 11/24 NP_001008844.1
DSPNM_001406591.1 linkuse as main transcriptc.1382T>C p.Ile461Thr missense_variant 11/11 NP_001393520.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkuse as main transcriptc.1382T>C p.Ile461Thr missense_variant 11/241 NM_004415.4 ENSP00000369129 P2P15924-1
DSPENST00000418664.2 linkuse as main transcriptc.1382T>C p.Ile461Thr missense_variant 11/241 ENSP00000396591 A2P15924-2
DSPENST00000710359.1 linkuse as main transcriptc.1382T>C p.Ile461Thr missense_variant 11/24 ENSP00000518230 A2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461742
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
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), LabcorpJun 01, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DSP-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 461 of the DSP protein (p.Ile461Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -
Arrhythmogenic right ventricular dysplasia 8 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 20, 2019The DSP c.1382T>C (p.Ile461Thr) missense variant is located in the SH3 desmosome binding domain. A literature search was performed for the gene, cDNA, and amino acid change. No publications were found based on this search. This variant is not found in the Genome Aggregation Database in a region of good sequencing coverage, so the variant is presumed to be rare. Based on the limited evidence, the p.Ile461Thr variant is classified as a variant of uncertain significance for arrhythmogenic right ventricular cardiomyopathy. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
D;.
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Benign
0.083
D
MetaRNN
Pathogenic
0.82
D;D
MetaSVM
Uncertain
-0.10
T
MutationAssessor
Benign
1.8
L;L
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-3.3
D;N
REVEL
Uncertain
0.59
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0070
D;D
Polyphen
0.99
D;.
Vest4
0.88
MutPred
0.30
Gain of phosphorylation at I461 (P = 0.0377);Gain of phosphorylation at I461 (P = 0.0377);
MVP
0.89
MPC
0.93
ClinPred
0.98
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.54
gMVP
0.74

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: rs1554106853; hg19: chr6-7568785; API