19-36039612-A-C

Variant names:

• chr19-36039612-A-C
• rs374686785
• NM_152658.3:c.383T>G

Variant summary

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

The NM_152658.3(THAP8):​c.383T>G​(p.Val128Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000351 in 1,509,876 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 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: THAP8 NM_152658.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0450
• 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=0.026028723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3	c.383T>G	p.Val128Gly	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.383T>G	p.Val128Gly	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000829 AC: 10 AN: 120586 AF XY: 0.0000806

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000177 AC: 24 AN: 1357698 Hom.: 0 Cov.: 33 AF XY: 0.0000165 AC XY: 11 AN XY: 665418

African (AFR) AF: 0.000724 AC: 22 AN: 30396

American (AMR) AF: 0.0000340 AC: 1 AN: 29380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22118

East Asian (EAS) AF: 0.00 AC: 0 AN: 35318

South Asian (SAS) AF: 0.00 AC: 0 AN: 72968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5436

European-Non Finnish (NFE) AF: 9.45e-7 AC: 1 AN: 1058100

Other (OTH) AF: 0.00 AC: 0 AN: 56110

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74346

African (AFR) AF: 0.000652 AC: 27 AN: 41432

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000762 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.000239 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000409 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.383T>G (p.V128G) alteration is located in exon 3 (coding exon 3) of the THAP8 gene. This alteration results from a T to G substitution at nucleotide position 383, causing the valine (V) at amino acid position 128 to be replaced by a glycine (G). 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	-0.32	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	5.5
DANN	Benign	0.45
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.19	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.63	N
PhyloP100		-0.045
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.32
Sift	Benign	0.16	T
Sift4G	Benign	0.068	T
Polyphen		0.60	P
Vest4		0.19
MVP		0.71
MPC		0.082
ClinPred		0.015	T
GERP RS		0.41
Varity_R		0.062
gMVP		0.43
Mutation Taster		=293/7	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: rs374686785; hg19: chr19-36530514;