rs142830104

chr6-109466257-A-G

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.1688T>C(p.Ile563Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000847 in 1,614,216 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I563I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (6 hom.)
• Consequence: ZBTB24 NM_014797.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 8.51

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=0.01947242).
• BP6: Variant 6-109466257-A-G is Benign according to our data. Variant chr6-109466257-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539538.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000624 (95/152322) while in subpopulation NFE AF= 0.001 (68/68034). AF 95% confidence interval is 0.000808. There are 0 homozygotes in gnomad4. There are 49 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB24	NM_014797.3	c.1688T>C	p.Ile563Thr	missense_variant	7/7	ENST00000230122.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB24	ENST00000230122.4	c.1688T>C	p.Ile563Thr	missense_variant	7/7	1	NM_014797.3	P1

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 95 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000999

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000797 AC: 200 AN: 250850 Hom.: 2 AF XY: 0.000929 AC XY: 126 AN XY: 135560

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.000839

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000871 AC: 1273 AN: 1461894 Hom.: 6 Cov.: 33 AF XY: 0.000956 AC XY: 695 AN XY: 727248

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00212

Gnomad4 FIN exome AF: 0.000768

Gnomad4 NFE exome AF: 0.000846

Gnomad4 OTH exome AF: 0.000977

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74492

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000999

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00101 Hom.: 1

Bravo AF: 0.000623

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000766 AC: 93

EpiCase AF: 0.00158

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Immunodeficiency-centromeric instability-facial anomalies syndrome 2 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 14, 2023	The ZBTB24 c.1688T>C; p.Ile563Thr variant (rs142830104), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 539538). This variant is found in the general population with an overall allele frequency of 0.08% (222/282,252 alleles, including 2 homozygotes) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.233). Due to limited information, the clinical significance of this variant is uncertain at this time. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

ZBTB24-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.95	D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.23
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.75	P
Vest4		0.58
MVP		0.34
MPC		0.56
ClinPred		0.051	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.069
gMVP		0.38

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: rs142830104; hg19: chr6-109787460;