8-42843070-C-T

Variant names:

• chr8-42843070-C-T
• rs267607112
• NM_018105.3:c.25G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3 PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_018105.3(THAP1):​c.25G>A​(p.Gly9Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000996206: Functional studies suggest that the p.Gly9Cys variant results in a reduction in the DNA-binding affinity of the THAP1-encoded protein (PMID:22844099).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G9C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THAP1 NM_018105.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.03
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• torsion dystonia 6

  Inheritance: AD, SD Classification: STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Laboratory for Molecular Medicine

ENSG00000286837 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000996206: Functional studies suggest that the p.Gly9Cys variant results in a reduction in the DNA-binding affinity of the THAP1-encoded protein (PMID: 22844099).
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 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-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1651.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.3716 (below the threshold of 3.09). Trascript score misZ: 2.0485 (below the threshold of 3.09). GenCC associations: The gene is linked to torsion dystonia 6.
• PP5: Variant 8-42843070-C-T is Pathogenic according to our data. Variant chr8-42843070-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 692056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018105.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP1	NM_018105.3	MANE Select	c.25G>A	p.Gly9Ser	missense	Exon 1 of 3	NP_060575.1	Q9NVV9-1
	THAP1	NM_199003.2		c.25G>A	p.Gly9Ser	missense	Exon 1 of 2	NP_945354.1	Q9NVV9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP1	ENST00000254250.7	TSL:1 MANE Select	c.25G>A	p.Gly9Ser	missense	Exon 1 of 3	ENSP00000254250.3	Q9NVV9-1
	THAP1	ENST00000345117.2	TSL:1	c.25G>A	p.Gly9Ser	missense	Exon 1 of 2	ENSP00000344966.2	Q9NVV9-2
	THAP1	ENST00000934698.1		c.25G>A	p.Gly9Ser	missense	Exon 1 of 3	ENSP00000604757.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Torsion dystonia 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.63
Sift	Benign	0.036	D
Sift4G	Benign	0.16	T
Polyphen		0.93	P
Vest4		0.51
MutPred		0.67		Gain of disorder (P = 0.0109)
MVP		0.67
MPC		1.4
ClinPred		0.97	D
GERP RS		4.7
PromoterAI		-0.11	Neutral
Varity_R		0.69
gMVP		0.65
Mutation Taster		=32/68	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267607112; hg19: chr8-42698213;