rs118204013

chr8-42839212-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_018105.3(THAP1):c.241T>C(p.Phe81Leu) variant causes a missense change involving the alteration of a 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F81V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: THAP1 NM_018105.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.04

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.

• PM1: In a zinc_finger_region THAP-type (size 80) in uniprot entity THAP1_HUMAN there are 53 pathogenic changes around while only 2 benign (96%) in NM_018105.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP1	NM_018105.3	c.241T>C	p.Phe81Leu	missense_variant	2/3	ENST00000254250.7
THAP1	NM_199003.2	c.72-876T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP1	ENST00000254250.7	c.241T>C	p.Phe81Leu	missense_variant	2/3	1	NM_018105.3	P1
THAP1	ENST00000345117.2	c.72-876T>C		intron_variant		1
THAP1	ENST00000529779.1	c.241T>C	p.Phe81Leu	missense_variant	2/3	5
THAP1	ENST00000532093.1	n.471T>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Torsion dystonia 6 Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 05, 2019	This sequence change replaces phenylalanine with leucine at codon 81 of the THAP1 protein (p.Phe81Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autosomal dominant dystonia in a family (PMID: 19182804). ClinVar contains an entry for this variant (Variation ID: 1646). This variant has been reported to have conflicting or insufficient data to determine the effect on THAP1 protein function (PMID:19182804, 22844099, 19345147, 28697333). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.99	D;.
Vest4		0.64
MutPred		0.95		Loss of phosphorylation at T84 (P = 0.1227);Loss of phosphorylation at T84 (P = 0.1227);
MVP		0.85
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.75

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

Other links and lift over

dbSNP: rs118204013; hg19: chr8-42694355;