rs139491074

Positions:

• chr6-109466195-T-A
• chr6-109466195-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_014797.3(ZBTB24):​c.1750A>T​(p.Met584Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,242 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: ZBTB24 NM_014797.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2 O:1
• Conservation: PhyloP100: 0.627

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008187324).
• BP6: Variant 6-109466195-T-A is Benign according to our data. Variant chr6-109466195-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 539534.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, not_provided=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000722 (110/152350) while in subpopulation NFE AF= 0.00137 (93/68018). AF 95% confidence interval is 0.00114. There are 1 homozygotes in gnomad4. There are 44 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB24	NM_014797.3	c.1750A>T	p.Met584Leu	missense_variant	7/7	ENST00000230122.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB24	ENST00000230122.4	c.1750A>T	p.Met584Leu	missense_variant	7/7	1	NM_014797.3	P1

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152232 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000756 AC: 190 AN: 251202 Hom.: 0 AF XY: 0.000766 AC XY: 104 AN XY: 135754

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00116 AC: 1694 AN: 1461892 Hom.: 1 Cov.: 33 AF XY: 0.00116 AC XY: 842 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.000957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000881

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00114

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152350 Hom.: 1 Cov.: 32 AF XY: 0.000591 AC XY: 44 AN XY: 74508

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000786

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000815 AC: 99

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 06-15-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 584 of the ZBTB24 protein (p.Met584Leu). This variant is present in population databases (rs139491074, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ZBTB24-related conditions. ClinVar contains an entry for this variant (Variation ID: 539534). 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 leucine 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2019	The ZBTB24 c.1750A>T; p.Met584Leu variant (rs139491074), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 539534). This variant is found in the general population with an overall allele frequency of 0.077% (219/282608 alleles) in the Genome Aggregation Database. The methionine at codon 584 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Met584Leu variant is uncertain at this time. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

ZBTB24: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.9
DANN	Benign	0.89
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.048
Sift	Benign	0.67	T
Sift4G	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.65		Loss of catalytic residue at M584 (P = 0.0049);
MVP		0.24
MPC		0.15
ClinPred		0.0087	T
GERP RS		0.48
Varity_R		0.051
gMVP		0.39

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: rs139491074; hg19: chr6-109787398;