Variant rs1131691345 details in Genebe, Genetics Data Aggregator

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

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 3.31

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]

THAP1 links:

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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 linkuse as main transcript	c.505C>T	p.Arg169Ter	stop_gained	3/3	ENST00000254250.7	NP_060575.1
THAP1	NM_199003.2 linkuse as main transcript	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 linkuse as main transcript	c.505C>T	p.Arg169Ter	stop_gained	3/3	1	NM_018105.3	ENSP00000254250	P1	Q9NVV9-1
THAP1	ENST00000345117.2 linkuse as main transcript	c.*147C>T		3_prime_UTR_variant	2/2	1		ENSP00000344966		Q9NVV9-2
THAP1	ENST00000529779.1 linkuse as main transcript			downstream_gene_variant		5		ENSP00000433912

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

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.:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

MutationTaster

Benign

1.0

D;D

Vest4

0.87

GERP RS

3.7

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over