8-42838099-G-C

Variant names:

• chr8-42838099-G-C
• rs1131691345
• NM_018105.3:c.505C>G
• THAP1 p.Arg169Gly

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_018105.3(THAP1):​c.505C>G​(p.Arg169Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THAP1 NM_018105.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.31
• Publications: 1 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: Orphanet, G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34521365).

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.505C>G	p.Arg169Gly	missense	Exon 3 of 3	NP_060575.1	Q9NVV9-1
	THAP1	NM_199003.2		c.*147C>G		3_prime_UTR	Exon 2 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.505C>G	p.Arg169Gly	missense	Exon 3 of 3	ENSP00000254250.3	Q9NVV9-1
	THAP1	ENST00000345117.2	TSL:1	c.*147C>G		3_prime_UTR	Exon 2 of 2	ENSP00000344966.2	Q9NVV9-2
	THAP1	ENST00000934698.1		c.439C>G	p.Arg147Gly	missense	Exon 3 of 3	ENSP00000604757.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.0058
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.3
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.41
Sift	Benign	0.059	T
Sift4G	Uncertain	0.040	D
Varity_R		0.22
gMVP		0.70
Mutation Taster		=70/30	polymorphism

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

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

Other links and lift over

dbSNP: rs1131691345;

hg19: chr8-42693242;