rs387907176

Variant names:

• chr8-42843025-T-C
• rs387907176
• NM_018105.3:c.70A>G
• THAP1 p.Lys24Glu

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_018105.3(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 NM_018105.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.01
• Publications: 6 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Orphanet, Laboratory for Molecular Medicine

ENSG00000286837 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_018105.3
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 8-42843025-T-C is Pathogenic according to our data. Variant chr8-42843025-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 31631.Status of the report is no_assertion_criteria_provided, 0 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.70A>G	p.Lys24Glu	missense splice_region	Exon 1 of 3	NP_060575.1	Q9NVV9-1
	THAP1	NM_199003.2		c.70A>G	p.Lys24Glu	missense splice_region	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.70A>G	p.Lys24Glu	missense splice_region	Exon 1 of 3	ENSP00000254250.3	Q9NVV9-1
	THAP1	ENST00000345117.2	TSL:1	c.70A>G	p.Lys24Glu	missense splice_region	Exon 1 of 2	ENSP00000344966.2	Q9NVV9-2
	THAP1	ENST00000934698.1		c.70A>G	p.Lys24Glu	missense splice_region	Exon 1 of 3	ENSP00000604757.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Torsion dystonia 6 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		5.0
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.077	T
PromoterAI		-0.13	Neutral
Varity_R		0.92
gMVP		0.78
Mutation Taster		=5/95	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387907176;

hg19: chr8-42698168;