Genetic Variant THAP8:p.Gln118Arg (chr19-36039642-T-C) – 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.353A>G(p.Gln118Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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: 7.3e-7 ( 0 hom. )

Consequence

THAP8
NM_152658.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.87

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:

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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=0.050474077).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3 link	c.353A>G	p.Gln118Arg	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.353A>G	p.Gln118Arg	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1		Q8NA92

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.35e-7

AC:

AN:

1360812

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

667754

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30340

American (AMR)

AF:

0.00

AC:

AN:

29286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22244

East Asian (EAS)

AF:

0.00

AC:

AN:

35434

South Asian (SAS)

AF:

0.00

AC:

AN:

72926

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1060876

Other (OTH)

AF:

0.0000178

AC:

AN:

56282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Feb 28, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.353A>G (p.Q118R) alteration is located in exon 3 (coding exon 3) of the THAP8 gene. This alteration results from a A to G substitution at nucleotide position 353, causing the glutamine (Q) at amino acid position 118 to be replaced by an arginine (R). 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

0.074

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.019

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.018

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0046

LIST_S2

Benign

0.27

M_CAP

Benign

0.017

MetaRNN

Benign

0.050

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.20

PhyloP100

-1.9

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.42

REVEL

Benign

0.17

Sift

Benign

0.27

Sift4G

Benign

0.42

Polyphen

0.0020

Vest4

0.015

MutPred

0.23

Gain of catalytic residue at Q118 (P = 0.0341);

MVP

0.34

MPC

0.066

ClinPred

0.17

GERP RS

-8.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.5

Varity_R

0.039

gMVP

0.17

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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19-36039642-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over