rs147441359

chr6-109481881-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 5.65

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]

ACMG classification

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=5, 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 GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB24	NM_014797.3	c.146G>A	p.Arg49Gln	missense_variant	2/7	ENST00000230122.4
ZBTB24	NM_001164313.2	c.146G>A	p.Arg49Gln	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB24	ENST00000230122.4	c.146G>A	p.Arg49Gln	missense_variant	2/7	1	NM_014797.3	P1

Frequencies

GnomAD3 genomes AF: 0.00610 AC: 928 AN: 152150 Hom.: 7 Cov.: 32

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.: 15 AF XY: 0.00654 AC XY: 889 AN XY: 135916

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.: 59 Cov.: 31 AF XY: 0.00730 AC XY: 5309 AN XY: 727246

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.: 7 Cov.: 32 AF XY: 0.00555 AC XY: 413 AN XY: 74460

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.: 8

Bravo AF: 0.00718

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00664 AC: 806

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0100

EpiControl AF: 0.00907

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 30, 2015	- -

Immunodeficiency-centromeric instability-facial anomalies syndrome 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

ZBTB24: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.77	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.27
Sift	Benign	0.054	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.84
MPC		0.72
ClinPred		0.011	T
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

Other links and lift over

dbSNP: rs147441359; hg19: chr6-109803084; COSMIC: COSV99038703;