chr19-36039349-G-A

Variant names:

• chr19-36039349-G-A
• rs1017141130
• NM_152658.3:c.646C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152658.3(THAP8):​c.646C>T​(p.Arg216Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,527,682 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: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: THAP8 NM_152658.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.378
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055854768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3	c.646C>T	p.Arg216Trp	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.646C>T	p.Arg216Trp	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000553 AC: 7 AN: 126502 AF XY: 0.0000434

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000426

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000495

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000305 AC: 42 AN: 1375302 Hom.: 0 Cov.: 30 AF XY: 0.0000339 AC XY: 23 AN XY: 678070

African (AFR) AF: 0.000128 AC: 4 AN: 31204

American (AMR) AF: 0.00 AC: 0 AN: 34646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24660

East Asian (EAS) AF: 0.000141 AC: 5 AN: 35388

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4942

European-Non Finnish (NFE) AF: 0.0000279 AC: 30 AN: 1074308

Other (OTH) AF: 0.0000349 AC: 2 AN: 57370

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152380 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74516

African (AFR) AF: 0.0000962 AC: 4 AN: 41598

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646C>T (p.R216W) 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 646, causing the arginine (R) at amino acid position 216 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	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.38
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.14	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.013	B
Vest4		0.16
MutPred		0.47		Gain of catalytic residue at L214 (P = 0.0036);
MVP		0.62
MPC		0.065
ClinPred		0.051	T
GERP RS		-1.6
Varity_R		0.047
gMVP		0.11
Mutation Taster		=99/1	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: rs1017141130; hg19: chr19-36530251;