Genetic Variant THAP8:p.Pro140Ser (chr19-36039577-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152658.3(THAP8):c.418C>T(p.Pro140Ser) 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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

THAP8
NM_152658.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.273

Publications

0 publications found

Variant links:

Genes affected

THAP8 (HGNC:23191): (THAP domain containing 8) Predicted to enable DNA binding activity and metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

THAP8 links:

ENSG00000267698 (HGNC:):

ENSG00000267698 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0587613).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3 link	c.418C>T	p.Pro140Ser	missense_variant	Exon 3 of 4	ENST00000292894.2	NP_689871.1	Q8NA92

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP8	ENST00000292894.2 link	c.418C>T	p.Pro140Ser	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1		Q8NA92

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1364456

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

669116

African (AFR)

AF:

0.00

AC:

AN:

30750

American (AMR)

AF:

0.00

AC:

AN:

30886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22566

East Asian (EAS)

AF:

0.00

AC:

AN:

35574

South Asian (SAS)

AF:

0.00

AC:

AN:

74456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5496

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1060184

Other (OTH)

AF:

0.00

AC:

AN:

56304

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.418C>T (p.P140S) alteration is located in exon 3 (coding exon 3) of the THAP8 gene. This alteration results from a C to T substitution at nucleotide position 418, causing the proline (P) at amino acid position 140 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.86

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.018

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.43

M_CAP

Benign

0.030

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.34

PhyloP100

-0.27

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.37

REVEL

Benign

0.12

Sift

Benign

0.17

Sift4G

Pathogenic

0.0

Polyphen

0.020

Vest4

0.069

MutPred

0.19

Loss of methylation at K141 (P = 0.0427);

MVP

0.52

MPC

0.067

ClinPred

0.071

GERP RS

0.31

Varity_R

0.025

gMVP

0.42

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over