19-36039534-G-A

Variant names:

• chr19-36039534-G-A
• rs113554294
• NM_152658.3:c.461C>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.461C>T​(p.Ala154Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000504 in 1,547,698 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 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: THAP8 NM_152658.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.254
• 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=0.04880455).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3	c.461C>T	p.Ala154Val	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.461C>T	p.Ala154Val	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000385

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: 0.0000473 AC: 8 AN: 169118 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000465

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000560

Gnomad OTH exome AF: 0.000234

GnomAD4 exome AF: 0.0000502 AC: 70 AN: 1395460 Hom.: 0 Cov.: 33 AF XY: 0.0000495 AC XY: 34 AN XY: 687466

African (AFR) AF: 0.000283 AC: 9 AN: 31762

American (AMR) AF: 0.00 AC: 0 AN: 35788

Ashkenazi Jewish (ASJ) AF: 0.000643 AC: 15 AN: 23328

East Asian (EAS) AF: 0.0000533 AC: 2 AN: 37502

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50040

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5562

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1075858

Other (OTH) AF: 0.000488 AC: 28 AN: 57368

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74378

African (AFR) AF: 0.0000482 AC: 2 AN: 41478

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

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

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

Alfa AF: 0.000260 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000585 AC: 7

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.461C>T (p.A154V) 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 461, causing the alanine (A) at amino acid position 154 to be replaced by a valine (V). 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	0.076
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	4.8
DANN	Uncertain	0.97
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.25
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.088
Sift	Benign	0.067	T
Sift4G	Benign	0.070	T
Polyphen		0.017	B
Vest4		0.097
MVP		0.45
MPC		0.074
ClinPred		0.049	T
GERP RS		-2.0
Varity_R		0.026
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: rs113554294; hg19: chr19-36530436;