Genetic Variant ZBTB46:p.Gly517Ser (chr20-63747151-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001369741.1(ZBTB46):c.1549G>A(p.Gly517Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000857 in 1,609,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 28)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

ZBTB46
NM_001369741.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.226

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01665017).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB46	NM_001369741.1 link	c.1549G>A	p.Gly517Ser	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.1549G>A	p.Gly517Ser	missense_variant	Exon 5 of 5	5	NM_001369741.1	ENSP00000245663.3	Q86UZ6
ZBTB46	ENST00000302995.2 link	c.1549G>A	p.Gly517Ser	missense_variant	Exon 5 of 7	2		ENSP00000303102.2	Q86UZ6
ZBTB46	ENST00000395104.5 link	c.1549G>A	p.Gly517Ser	missense_variant	Exon 4 of 4	2		ENSP00000378536.1	Q86UZ6

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151882

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000587

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000150

AC:

AN:

233026

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

128282

show subpopulations

Gnomad AFR exome

AF:

0.0000709

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000906

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000892

AC:

130

AN:

1457992

Hom.:

Cov.:

AF XY:

0.0000883

AC XY:

AN XY:

725196

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000202

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000933

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.0000630

Gnomad4 OTH exome

AF:

0.0000665

GnomAD4 genome

AF:

0.0000526

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000588

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000176

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000202

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1549G>A (p.G517S) 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 1549, causing the glycine (G) at amino acid position 517 to be replaced by a serine (S). 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

-0.48

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.019

T;T;T

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.41

.;.;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.90

L;L;L

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.25

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.70

T;T;T

Sift4G

Benign

0.62

T;T;T

Polyphen

0.88

P;P;P

Vest4

0.19

MVP

0.10

MPC

0.073

ClinPred

0.064

GERP RS

4.2

Varity_R

0.063

gMVP

0.23

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