19-36039528-G-T

Variant names:

• chr19-36039528-G-T
• rs75451634
• NM_152658.3:c.467C>A

Variant summary

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

The NM_152658.3(THAP8):​c.467C>A​(p.Thr156Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,556,050 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: THAP8 NM_152658.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50
• Publications: 4 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=0.00634405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3	c.467C>A	p.Thr156Asn	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.467C>A	p.Thr156Asn	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1

Frequencies

GnomAD3 genomes AF: 0.000637 AC: 97 AN: 152260 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000274 AC: 49 AN: 178584 AF XY: 0.000156

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00165

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000389

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000123 AC: 172 AN: 1403672 Hom.: 0 Cov.: 33 AF XY: 0.0000939 AC XY: 65 AN XY: 692450

African (AFR) AF: 0.00272 AC: 87 AN: 31942

American (AMR) AF: 0.000109 AC: 4 AN: 36638

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 31 AN: 23562

East Asian (EAS) AF: 0.00 AC: 0 AN: 37948

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50494

Middle Eastern (MID) AF: 0.00143 AC: 8 AN: 5582

European-Non Finnish (NFE) AF: 0.00000925 AC: 10 AN: 1080558

Other (OTH) AF: 0.000520 AC: 30 AN: 57724

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152378 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74512

African (AFR) AF: 0.00190 AC: 79 AN: 41598

American (AMR) AF: 0.000261 AC: 4 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68040

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.0000719 Hom.: 0

Bravo AF: 0.000827

ExAC AF: 0.000250 AC: 30

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.467C>A (p.T156N) alteration is located in exon 3 (coding exon 3) of the THAP8 gene. This alteration results from a C to A substitution at nucleotide position 467, causing the threonine (T) at amino acid position 156 to be replaced by an asparagine (N). 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	0.095
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.4
DANN	Benign	0.94
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.11
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.020	D
Polyphen		0.40	B
Vest4		0.086
MVP		0.69
MPC		0.16
ClinPred		0.0072	T
GERP RS		2.2
Varity_R		0.057
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75451634; hg19: chr19-36530430;