rs1554599707

Variant names:

• chr8-42839292-C-G
• rs1554599707
• NM_018105.3:c.161G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_018105.3(THAP1):​c.161G>C​(p.Cys54Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THAP1 NM_018105.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.14
• Publications: 0 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• 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: MetaRNN computational evidence supports a deleterious effect, 0.994

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.161G>C	p.Cys54Ser	missense	Exon 2 of 3	NP_060575.1	Q9NVV9-1
	THAP1	NM_199003.2		c.72-956G>C		intron	N/A	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.161G>C	p.Cys54Ser	missense	Exon 2 of 3	ENSP00000254250.3	Q9NVV9-1
	THAP1	ENST00000345117.2	TSL:1	c.72-956G>C		intron	N/A	ENSP00000344966.2	Q9NVV9-2
	THAP1	ENST00000934698.1		c.161G>C	p.Cys54Ser	missense	Exon 2 of 3	ENSP00000604757.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		7.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-9.4	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.95		Gain of disorder (P = 0.0188)
MVP		0.81
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.93
Mutation Taster		=15/85	disease causing

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: rs1554599707; hg19: chr8-42694435;