rs144189559

Positions:

chr6-109481726-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The ENST00000230122.4(ZBTB24):c.301G>A(p.Ala101Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,614,088 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

ZBTB24
ENST00000230122.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44

Variant links:

Genes affected

ZBTB24 (HGNC:21143): (zinc finger and BTB domain containing 24) Predicted to enable DNA-binding transcription factor activity and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be located in nucleus. Implicated in immunodeficiency-centromeric instability-facial anomalies syndrome 2. [provided by Alliance of Genome Resources, Apr 2022]

ZBTB24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05568838).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000276 (42/152194) while in subpopulation AMR AF= 0.000589 (9/15278). AF 95% confidence interval is 0.000307. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB24	NM_014797.3 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	2/7	ENST00000230122.4	NP_055612.2
ZBTB24	NM_001164313.2 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	2/2		NP_001157785.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB24	ENST00000230122.4 linkuse as main transcript	c.301G>A	p.Ala101Thr	missense_variant	2/7	1	NM_014797.3	ENSP00000230122	P1	O43167-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

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:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000175

AC:

AN:

251488

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000231

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:

0.000308

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000337

AC:

493

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000246

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:

0.000419

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000276

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000260

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 03, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 101 of the ZBTB24 protein (p.Ala101Thr). This variant is present in population databases (rs144189559, gnomAD 0.03%). This missense change has been observed in individual(s) with immunodeficiency-centromeric instability-facial anomalies syndrome (PMID: 33995370). ClinVar contains an entry for this variant (Variation ID: 570181). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.082

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.74

M_CAP

Benign

0.0074

MetaRNN

Benign

0.056

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.47

MutationTaster

Benign

0.88

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.15

REVEL

Benign

0.034

Sift

Benign

0.28

Sift4G

Benign

0.19

Polyphen

0.0080

Vest4

0.20

MVP

0.067

MPC

0.18

ClinPred

0.036

GERP RS

3.9

Varity_R

0.051

gMVP

0.30

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