Genetic Variant NM_152658.3:c.547C>T (chr19-36039448-G-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_152658.3(THAP8):c.547C>T(p.Arg183Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000244 in 1,595,584 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 1 hom. )

Consequence

THAP8
NM_152658.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.342

Publications

0 publications found

Variant links:

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]

THAP8 links:

ENSG00000267698 (HGNC:):

ENSG00000267698 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3200124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP8	NM_152658.3 link	c.547C>T	p.Arg183Trp	missense_variant	Exon 3 of 4	ENST00000292894.2	NP_689871.1	Q8NA92

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP8	ENST00000292894.2 link	c.547C>T	p.Arg183Trp	missense_variant	Exon 3 of 4	1	NM_152658.3	ENSP00000292894.1		Q8NA92

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000511

AC:

AN:

215308

AF XY:

0.0000680

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000236

AC:

AN:

1443344

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

716400

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33012

American (AMR)

AF:

0.00

AC:

AN:

42662

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25586

East Asian (EAS)

AF:

0.00

AC:

AN:

38846

South Asian (SAS)

AF:

0.000167

AC:

AN:

83752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0000181

AC:

AN:

1102810

Other (OTH)

AF:

0.00

AC:

AN:

59578

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000281

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 30, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.547C>T (p.R183W) 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 547, causing the arginine (R) at amino acid position 183 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

0.24

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.014

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.32

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.0

PhyloP100

0.34

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.6

REVEL

Benign

0.18

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.27

MutPred

0.35

Loss of methylation at R182 (P = 0.2098);

MVP

0.72

MPC

0.39

ClinPred

0.26

GERP RS

0.66

Varity_R

0.088

gMVP

0.37

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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NM_152658.3:c.547C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over