16-67842852-G-T

Position:

chr16-67842852-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_020457.3(THAP11):c.298G>T(p.Ala100Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000406 in 1,601,522 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 1 hom. )

Consequence

THAP11
NM_020457.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.05

Variant links:

Genes affected

THAP11 (HGNC:23194): (THAP domain containing 11) The protein encoded by this gene contains a THAP domain, which is a conserved DNA-binding domain that has striking similarity to the site-specific DNA-binding domain (DBD) of Drosophila P element transposases. [provided by RefSeq, Jul 2008]

THAP11 links:

CENPT (HGNC:25787): (centromere protein T) The centromere is a specialized chromatin domain, present throughout the cell cycle, that acts as a platform on which the transient assembly of the kinetochore occurs during mitosis. All active centromeres are characterized by the presence of long arrays of nucleosomes in which CENPA (MIM 117139) replaces histone H3 (see MIM 601128). CENPT is an additional factor required for centromere assembly (Foltz et al., 2006 [PubMed 16622419]).[supplied by OMIM, Mar 2008]

CENPT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20649669).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THAP11	NM_020457.3 linkuse as main transcript	c.298G>T	p.Ala100Ser	missense_variant	1/1	ENST00000303596.3	NP_065190.2
CENPT	NM_025082.4 linkuse as main transcript	c.-492+4549C>A		intron_variant		ENST00000562787.6	NP_079358.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THAP11	ENST00000303596.3 linkuse as main transcript	c.298G>T	p.Ala100Ser	missense_variant	1/1		NM_020457.3	ENSP00000304689	P1
CENPT	ENST00000562787.6 linkuse as main transcript	c.-492+4549C>A		intron_variant		2	NM_025082.4	ENSP00000457810	P1	Q96BT3-1

Frequencies

GnomAD3 genomes

AF:

0.0000400

AC:

AN:

150162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000661

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:

0.0000745

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000897

AC:

AN:

222912

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

124066

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000891

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.00108

GnomAD4 exome

AF:

0.0000407

AC:

AN:

1451360

Hom.:

Cov.:

AF XY:

0.0000471

AC XY:

AN XY:

722156

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000902

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000500

GnomAD4 genome

AF:

0.0000400

AC:

AN:

150162

Hom.:

Cov.:

AF XY:

0.0000547

AC XY:

AN XY:

73178

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000661

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000745

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000101

AC:

EpiCase

AF:

0.000165

EpiControl

AF:

0.000180

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 2021

The c.298G>T (p.A100S) alteration is located in exon 1 (coding exon 1) of the THAP11 gene. This alteration results from a G to T substitution at nucleotide position 298, causing the alanine (A) at amino acid position 100 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with THAP11-related conditions. This variant is present in population databases (rs754275294, gnomAD 0.01%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 100 of the THAP11 protein (p.Ala100Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

Eigen

Benign

0.034

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.55

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.21

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.20

REVEL

Benign

0.037

Sift

Benign

0.16

Sift4G

Benign

0.53

Polyphen

0.19

Vest4

0.23

MutPred

0.33

Gain of phosphorylation at A100 (P = 0.0033);

MVP

0.62

MPC

1.1

ClinPred

0.089

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.11

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over