rs147441359

Positions:

chr6-109481881-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000230122.4(ZBTB24):c.146G>A(p.Arg49Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00731 in 1,614,160 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0061 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0074 ( 59 hom. )

Consequence

ZBTB24
ENST00000230122.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 5.65

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014561236).

BP6

Variant 6-109481881-C-T is Benign according to our data. Variant chr6-109481881-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252685.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00609 (927/152268) while in subpopulation AMR AF= 0.0111 (170/15294). AF 95% confidence interval is 0.00975. There are 7 homozygotes in gnomad4. There are 413 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB24	NM_014797.3 linkuse as main transcript	c.146G>A	p.Arg49Gln	missense_variant	2/7	ENST00000230122.4	NP_055612.2
ZBTB24	NM_001164313.2 linkuse as main transcript	c.146G>A	p.Arg49Gln	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.146G>A	p.Arg49Gln	missense_variant	2/7	1	NM_014797.3	ENSP00000230122	P1	O43167-1

Frequencies

GnomAD3 genomes

AF:

0.00610

AC:

928

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00171

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0111

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00860

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00672

AC:

1691

AN:

251482

Hom.:

AF XY:

0.00654

AC XY:

889

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00795

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00222

Gnomad FIN exome

AF:

0.00314

Gnomad NFE exome

AF:

0.00909

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.00744

AC:

10871

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00730

AC XY:

5309

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00167

Gnomad4 AMR exome

AF:

0.00778

Gnomad4 ASJ exome

AF:

0.0147

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00201

Gnomad4 FIN exome

AF:

0.00268

Gnomad4 NFE exome

AF:

0.00830

Gnomad4 OTH exome

AF:

0.00796

GnomAD4 genome

AF:

0.00609

AC:

927

AN:

152268

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

413

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00171

Gnomad4 AMR

AF:

0.0111

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00859

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.00850

Hom.:

Bravo

AF:

0.00718

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00664

AC:

806

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0100

EpiControl

AF:

0.00907

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 30, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 05, 2022	Variant summary: ZBTB24 c.146G>A (p.Arg49Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0067 in 251482 control chromosomes, predominantly at a frequency of 0.0091 within the Non-Finnish European subpopulation in the gnomAD database, including 10 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in ZBTB24 causing ICF Syndrome, Type 2 phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although reported in the literature, to our knowledge, no penetrant association of c.146G>A in individuals affected with ICF Syndrome, Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Immunodeficiency-centromeric instability-facial anomalies syndrome 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Kabuki syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2024

ZBTB24: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

MetaRNN

Benign

0.015

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.3

MutationTaster

Benign

0.77

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.40

REVEL

Benign

0.27

Sift

Benign

0.054

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.68

MVP

0.84

MPC

0.72

ClinPred

0.011

GERP RS

4.7

Varity_R

0.16

gMVP

0.47

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