rs267607112

chr8-42843070-C-Achr8-42843070-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_018105.3(THAP1):c.25G>T(p.Gly9Cys) variant causes a missense change. 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THAP1 NM_018105.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.03

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 1 uncertain in NM_018105.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-42843070-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 692056.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 8-42843070-C-A is Pathogenic according to our data. Variant chr8-42843070-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1651.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-42843070-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP1	NM_018105.3	c.25G>T	p.Gly9Cys	missense_variant	1/3	ENST00000254250.7
LOC124901940	XR_007060901.1	n.137C>A		non_coding_transcript_exon_variant	1/2
THAP1	NM_199003.2	c.25G>T	p.Gly9Cys	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP1	ENST00000254250.7	c.25G>T	p.Gly9Cys	missense_variant	1/3	1	NM_018105.3	P1
THAP1	ENST00000345117.2	c.25G>T	p.Gly9Cys	missense_variant	1/2	1
	ENST00000669010.1	n.82C>A		non_coding_transcript_exon_variant	1/2
THAP1	ENST00000529779.1	c.25G>T	p.Gly9Cys	missense_variant	1/3	5

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

Jan 19, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
Cadd	Pathogenic	32
Dann	Benign	0.96
DEOGEN2	Pathogenic	0.84	D;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.86	D;T;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	0.80	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0050	D;D;T
Sift4G	Uncertain	0.014	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.85
MutPred		0.89		Loss of disorder (P = 0.1512);Loss of disorder (P = 0.1512);Loss of disorder (P = 0.1512);
MVP		0.84
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.87
gMVP		0.79

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: rs267607112; hg19: chr8-42698213;