rs147441359

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014797.3(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
NM_014797.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.65

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

immunodeficiency-centromeric instability-facial anomalies syndrome 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
immunodeficiency-centromeric instability-facial anomalies syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ZBTB24 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 252685.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB24	NM_014797.3 link	c.146G>A	p.Arg49Gln	missense_variant	Exon 2 of 7	ENST00000230122.4	NP_055612.2	O43167-1
ZBTB24	NM_001164313.2 link	c.146G>A	p.Arg49Gln	missense_variant	Exon 2 of 2		NP_001157785.1	O43167-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB24	ENST00000230122.4 link	c.146G>A	p.Arg49Gln	missense_variant	Exon 2 of 7	1	NM_014797.3	ENSP00000230122.4		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

GnomAD2 exomes

AF:

0.00672

AC:

1691

AN:

251482

AF XY:

0.00654

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 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

African (AFR)

AF:

0.00167

AC:

AN:

33480

American (AMR)

AF:

0.00778

AC:

348

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

385

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00201

AC:

173

AN:

86256

European-Finnish (FIN)

AF:

0.00268

AC:

143

AN:

53420

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00830

AC:

9228

AN:

1112012

Other (OTH)

AF:

0.00796

AC:

481

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

684

1367

2051

2734

3418

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00609

AC:

927

AN:

152268

Hom.:

Cov.:

AF XY:

0.00555

AC XY:

413

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00171

AC:

AN:

41544

American (AMR)

AF:

0.0111

AC:

170

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00235

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00859

AC:

584

AN:

68020

Other (OTH)

AF:

0.00662

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

143

191

239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00786

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

Jul 30, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 05, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kabuki syndrome 1

Uncertain:1

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

5.6

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

Mutation Taster

=99/1

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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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