8-42838315-G-A

Position:

• chr8-42838315-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_018105.3(THAP1):​c.289C>T​(p.Gln97*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THAP1 NM_018105.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.65

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-42838315-G-A is Pathogenic according to our data. Variant chr8-42838315-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 532262.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THAP1	NM_018105.3	c.289C>T	p.Gln97*	stop_gained	3/3	ENST00000254250.7	NP_060575.1
THAP1	NM_199003.2	c.93C>T	p.His31His	synonymous_variant	2/2		NP_945354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THAP1	ENST00000254250.7	c.289C>T	p.Gln97*	stop_gained	3/3	1	NM_018105.3	ENSP00000254250.3
THAP1	ENST00000345117.2	c.93C>T	p.His31His	synonymous_variant	2/2	1		ENSP00000344966.2
THAP1	ENST00000529779.1	c.268-84C>T		intron_variant		5		ENSP00000433912.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Torsion dystonia 6 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 21, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 532262). This premature translational stop signal has been observed in individuals with dystonia (PMID: 24976531). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln97*) in the THAP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 117 amino acid(s) of the THAP1 protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.19	N
Vest4		0.67
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs1554599616; hg19: chr8-42693458;