Genetic Variant ZBTB46:p.Arg573Gln (chr20-63746982-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001369741.1(ZBTB46):c.1718G>A(p.Arg573Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,605,090 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 2 hom. )

Consequence

ZBTB46
NM_001369741.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0430

Variant links:

Genes affected

ZBTB46 (HGNC:16094): (zinc finger and BTB domain containing 46) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription 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 regulation of leukocyte differentiation. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZBTB46 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077747703).

BS2

High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB46	NM_001369741.1 link	c.1718G>A	p.Arg573Gln	missense_variant	Exon 5 of 5	ENST00000245663.9	NP_001356670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZBTB46	ENST00000245663.9 link	c.1718G>A	p.Arg573Gln	missense_variant	Exon 5 of 5	5	NM_001369741.1	ENSP00000245663.3	Q86UZ6
ZBTB46	ENST00000302995.2 link	c.1718G>A	p.Arg573Gln	missense_variant	Exon 5 of 7	2		ENSP00000303102.2	Q86UZ6
ZBTB46	ENST00000395104.5 link	c.1718G>A	p.Arg573Gln	missense_variant	Exon 4 of 4	2		ENSP00000378536.1	Q86UZ6

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000387

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000557

AC:

130

AN:

233356

Hom.:

AF XY:

0.000545

AC XY:

AN XY:

128394

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00123

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000447

Gnomad SAS exome

AF:

0.0000992

Gnomad FIN exome

AF:

0.00117

Gnomad NFE exome

AF:

0.000529

Gnomad OTH exome

AF:

0.000346

GnomAD4 exome

AF:

0.000357

AC:

519

AN:

1452934

Hom.:

Cov.:

AF XY:

0.000404

AC XY:

292

AN XY:

722898

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00110

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000582

Gnomad4 FIN exome

AF:

0.00109

Gnomad4 NFE exome

AF:

0.000348

Gnomad4 OTH exome

AF:

0.000299

GnomAD4 genome

AF:

0.000473

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000603

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000467

AC:

ExAC

AF:

0.000456

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000475

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1718G>A (p.R573Q) alteration is located in exon 5 (coding exon 4) of the ZBTB46 gene. This alteration results from a G to A substitution at nucleotide position 1718, causing the arginine (R) at amino acid position 573 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.66

DANN

Benign

0.90

DEOGEN2

Benign

0.017

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.38

.;.;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.0078

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.69

N;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.29

N;N;N

REVEL

Benign

0.033

Sift

Benign

0.50

T;T;T

Sift4G

Benign

0.60

T;T;T

Polyphen

0.0030

B;B;B

Vest4

0.10

MVP

0.068

MPC

0.080

ClinPred

0.010

GERP RS

-3.0

Varity_R

0.023

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over