rs387907176

Positions:

• chr8-42843025-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The ENST00000254250.7(THAP1):​c.70A>G​(p.Lys24Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: THAP1 ENST00000254250.7 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.01

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in ENST00000254250.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.852
• PP5: Variant 8-42843025-T-C is Pathogenic according to our data. Variant chr8-42843025-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 31631.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-42843025-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THAP1	NM_018105.3	c.70A>G	p.Lys24Glu	missense_variant, splice_region_variant	1/3	ENST00000254250.7	NP_060575.1
LOC124901940	XR_007060901.1	n.92T>C		non_coding_transcript_exon_variant	1/2
THAP1	NM_199003.2	c.70A>G	p.Lys24Glu	missense_variant, splice_region_variant	1/2		NP_945354.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THAP1	ENST00000254250.7	c.70A>G	p.Lys24Glu	missense_variant, splice_region_variant	1/3	1	NM_018105.3	ENSP00000254250	P1
THAP1	ENST00000345117.2	c.70A>G	p.Lys24Glu	missense_variant, splice_region_variant	1/2	1		ENSP00000344966
	ENST00000669010.1	n.37T>C		non_coding_transcript_exon_variant	1/2
THAP1	ENST00000529779.1	c.70A>G	p.Lys24Glu	missense_variant, splice_region_variant	1/3	5		ENSP00000433912

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Torsion dystonia 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	31
DANN	Benign	0.97
DEOGEN2	Uncertain	0.76	D;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.90	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D;D;N
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.077	T;D;T
Polyphen		0.12	B;.;P
Vest4		0.84
MutPred		0.63		Loss of methylation at K24 (P = 2e-04);Loss of methylation at K24 (P = 2e-04);Loss of methylation at K24 (P = 2e-04);
MVP		0.96
MPC		1.1
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.92
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.060		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: rs387907176; hg19: chr8-42698168;