rs61731736

chr6-109466273-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014797.3(ZBTB24):c.1672G>A(p.Asp558Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00269 in 1,614,196 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (11 hom.)
• Consequence: ZBTB24 NM_014797.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.71

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005057752).
• BP6: Variant 6-109466273-C-T is Benign according to our data. Variant chr6-109466273-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 539542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-109466273-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (362/152304) while in subpopulation NFE AF= 0.00319 (217/68038). AF 95% confidence interval is 0.00284. There are 1 homozygotes in gnomad4. There are 155 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZBTB24	NM_014797.3	c.1672G>A	p.Asp558Asn	missense_variant	7/7	ENST00000230122.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZBTB24	ENST00000230122.4	c.1672G>A	p.Asp558Asn	missense_variant	7/7	1	NM_014797.3	P1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152186 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00261 AC: 654 AN: 250798 Hom.: 3 AF XY: 0.00258 AC XY: 349 AN XY: 135500

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000555

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00312

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00272 AC: 3983 AN: 1461892 Hom.: 11 Cov.: 33 AF XY: 0.00268 AC XY: 1952 AN XY: 727246

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00288

Gnomad4 OTH exome AF: 0.00329

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152304 Hom.: 1 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74482

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00350 Hom.: 0

Bravo AF: 0.00260

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00252 AC: 306

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00391

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ZBTB24: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

ZBTB24-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 12, 2021

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	Benign	0.16
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0033
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.28	N
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.099
Sift	Benign	0.16	T
Sift4G	Benign	0.27	T
Polyphen		0.033	B
Vest4		0.099
MVP		0.17
MPC		0.17
ClinPred		0.014	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.053
gMVP		0.48

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: rs61731736; hg19: chr6-109787476;