19-36039388-G-A

Variant names:

• chr19-36039388-G-A
• rs761966430
• NM_152658.3:c.607C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152658.3(THAP8):​c.607C>T​(p.Arg203Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000668 in 1,543,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: THAP8 NM_152658.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.395
• Publications: 0 publications found

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]

ENSG00000267698 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06433985).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3	c.607C>T	p.Arg203Trp	missense_variant	Exon 3 of 4	ENST00000292894.2	NP_689871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP8	ENST00000292894.2	c.607C>T	p.Arg203Trp	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152264 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000352 AC: 5 AN: 142196 AF XY: 0.0000129

Gnomad AFR exome AF: 0.000140

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000110

Gnomad NFE exome AF: 0.0000546

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000626 AC: 87 AN: 1390776 Hom.: 0 Cov.: 30 AF XY: 0.0000451 AC XY: 31 AN XY: 686696

African (AFR) AF: 0.000347 AC: 11 AN: 31670

American (AMR) AF: 0.0000278 AC: 1 AN: 36034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25100

East Asian (EAS) AF: 0.00 AC: 0 AN: 35874

South Asian (SAS) AF: 0.00 AC: 0 AN: 79488

European-Finnish (FIN) AF: 0.000127 AC: 5 AN: 39254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.0000537 AC: 58 AN: 1079864

Other (OTH) AF: 0.000207 AC: 12 AN: 57922

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74392

African (AFR) AF: 0.000362 AC: 15 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000189 AC: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.607C>T (p.R203W) 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 607, causing the arginine (R) at amino acid position 203 to be replaced by a tryptophan (W). 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.40
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.92	P
Vest4		0.29
MutPred		0.27		Gain of catalytic residue at L201 (P = 0.0039);
MVP		0.73
MPC		0.17
ClinPred		0.19	T
GERP RS		0.59
Varity_R		0.10
gMVP		0.12
Mutation Taster		=95/5	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

Other links and lift over

dbSNP: rs761966430; hg19: chr19-36530290;