rs1131691345
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The ENST00000254250.7(THAP1):c.505C>T(p.Arg169Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
THAP1
ENST00000254250.7 stop_gained
ENST00000254250.7 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.31
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 Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 8-42838099-G-A is Pathogenic according to our data. Variant chr8-42838099-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 429366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
THAP1 | NM_018105.3 | c.505C>T | p.Arg169Ter | stop_gained | 3/3 | ENST00000254250.7 | NP_060575.1 | |
THAP1 | NM_199003.2 | c.*147C>T | 3_prime_UTR_variant | 2/2 | NP_945354.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
THAP1 | ENST00000254250.7 | c.505C>T | p.Arg169Ter | stop_gained | 3/3 | 1 | NM_018105.3 | ENSP00000254250 | P1 | |
THAP1 | ENST00000345117.2 | c.*147C>T | 3_prime_UTR_variant | 2/2 | 1 | ENSP00000344966 | ||||
THAP1 | ENST00000529779.1 | downstream_gene_variant | 5 | ENSP00000433912 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727242
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Torsion dystonia 6 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 29, 2018 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Other truncations (p.Arg172Lysfs*7 and p.Asp191Thrfs*9) that lie downstream of this variant have been reported in individuals affected with dystonia (PMID: 21520283, 21847143). This variant has been observed to segregate with clinical features of dystonia in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 429366). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the THAP1 gene (p.Arg169*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 45 amino acids of the THAP1 protein. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2020 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 45 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
Vest4
GERP RS
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