rs374512193

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_StrongBS2

The NM_018105.3(THAP1):ā€‹c.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

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.11
Variant links:
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]

Genome browser will be placed here

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
THAP1NM_018105.3 linkuse as main transcriptc.427A>G p.Met143Val missense_variant 3/3 ENST00000254250.7
THAP1NM_199003.2 linkuse as main transcriptc.*69A>G 3_prime_UTR_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
THAP1ENST00000254250.7 linkuse as main transcriptc.427A>G p.Met143Val missense_variant 3/31 NM_018105.3 P1Q9NVV9-1
THAP1ENST00000345117.2 linkuse as main transcriptc.*69A>G 3_prime_UTR_variant 2/21 Q9NVV9-2
THAP1ENST00000529779.1 linkuse as main transcriptc.322A>G p.Met108Val missense_variant 3/35

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152160
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251490
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135922
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000435
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000342
AC:
50
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.0000371
AC XY:
27
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000526
AC:
8
AN:
152160
Hom.:
0
Cov.:
33
AF XY:
0.0000673
AC XY:
5
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000500
Hom.:
0
Bravo
AF:
0.0000340
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 submitterclinical testingFoundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human GeneticsDec 31, 2019A 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 submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 22, 2023This 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). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jul 21, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.051
BayesDel_addAF
Uncertain
0.021
T
BayesDel_noAF
Uncertain
0.12
CADD
Benign
17
DANN
Benign
0.43
DEOGEN2
Benign
0.037
T;.
Eigen
Benign
-0.42
Eigen_PC
Benign
-0.19
FATHMM_MKL
Uncertain
0.76
D
LIST_S2
Benign
0.78
T;T
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.066
T;T
MetaSVM
Benign
-0.38
T
MutationAssessor
Benign
-0.69
N;.
MutationTaster
Benign
1.0
D;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
0.10
N;N
REVEL
Uncertain
0.44
Sift
Benign
1.0
T;T
Sift4G
Benign
0.32
T;T
Polyphen
0.0
B;.
Vest4
0.70
MVP
0.88
MPC
0.57
ClinPred
0.050
T
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.026
gMVP
0.26

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: rs374512193; hg19: chr8-42693320; API