rs374512193
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2
The NM_018105.3(THAP1):āc.427A>Gā(p.Met143Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000359 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 33)
Exomes š: 0.000034 ( 0 hom. )
Consequence
THAP1
NM_018105.3 missense
NM_018105.3 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 5.11
Genes affected
THAP1 (HGNC:20856): (THAP domain containing 1) The protein encoded by this gene contains a THAP domain, a conserved DNA-binding domain. This protein colocalizes with the apoptosis response protein PAWR/PAR-4 in promyelocytic leukemia (PML) nuclear bodies, and functions as a proapoptotic factor that links PAWR to PML nuclear bodies. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PM1
?
In a coiled_coil_region (size 51) in uniprot entity THAP1_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_018105.3
BP4
?
Computational evidence support a benign effect (MetaRNN=0.06602925).
BS2
?
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
THAP1 | NM_018105.3 | c.427A>G | p.Met143Val | missense_variant | 3/3 | ENST00000254250.7 | |
THAP1 | NM_199003.2 | c.*69A>G | 3_prime_UTR_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
THAP1 | ENST00000254250.7 | c.427A>G | p.Met143Val | missense_variant | 3/3 | 1 | NM_018105.3 | P1 | |
THAP1 | ENST00000345117.2 | c.*69A>G | 3_prime_UTR_variant | 2/2 | 1 | ||||
THAP1 | ENST00000529779.1 | c.322A>G | p.Met108Val | missense_variant | 3/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152160Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251490Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
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GnomAD4 exome AF: 0.0000342 AC: 50AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 727242
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74336
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Torsion dystonia 6 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Dec 31, 2019 | A heterozygous missense variation in exon 3 of the THAP1 gene that results in the amino acid substitution of Valine for Methionine at codon 143 was detected. The observed variant c.427A>G (p.Met143Val) has not been reported in the 1000 genomes database and has a minor allele frequency of 0.007% in the ExAC database. The in silico prediction of the variant is damaging by LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 22, 2023 | This missense change has been observed in individual(s) with dystonia (PMID: 20669277, 27913194). ClinVar contains an entry for this variant (Variation ID: 225489). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. This variant is present in population databases (rs374512193, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 143 of the THAP1 protein (p.Met143Val). - |
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 21, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.
MutationTaster
Benign
D;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at