rs969373062
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_004415.4(DSP):c.422G>A(p.Arg141Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,461,430 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
DSP
NM_004415.4 missense, splice_region
NM_004415.4 missense, splice_region
Scores
1
4
14
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.97
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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DSP | NM_004415.4 | c.422G>A | p.Arg141Lys | missense_variant, splice_region_variant | 3/24 | ENST00000379802.8 | NP_004406.2 | |
DSP | NM_001319034.2 | c.422G>A | p.Arg141Lys | missense_variant, splice_region_variant | 3/24 | NP_001305963.1 | ||
DSP | NM_001008844.3 | c.422G>A | p.Arg141Lys | missense_variant, splice_region_variant | 3/24 | NP_001008844.1 | ||
DSP | NM_001406591.1 | c.422G>A | p.Arg141Lys | missense_variant, splice_region_variant | 3/11 | NP_001393520.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DSP | ENST00000379802.8 | c.422G>A | p.Arg141Lys | missense_variant, splice_region_variant | 3/24 | 1 | NM_004415.4 | ENSP00000369129.3 | ||
DSP | ENST00000418664.2 | c.422G>A | p.Arg141Lys | missense_variant, splice_region_variant | 3/24 | 1 | ENSP00000396591.2 | |||
DSP | ENST00000710359.1 | c.422G>A | p.Arg141Lys | missense_variant, splice_region_variant | 3/24 | ENSP00000518230.1 | ||||
DSP | ENST00000683563.1 | n.314G>A | splice_region_variant, non_coding_transcript_exon_variant | 3/4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461430Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726994
GnomAD4 exome
AF:
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2
AN:
1461430
Hom.:
Cov.:
33
AF XY:
AC XY:
0
AN XY:
726994
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | In 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant has not been reported in the literature in individuals affected with DSP-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 141 of the DSP protein (p.Arg141Lys). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MutPred
Gain of ubiquitination at R141 (P = 0.0185);Gain of ubiquitination at R141 (P = 0.0185);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at