Genetic Variant ZBTB46:p.Asp540Tyr (chr20-63747082-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001369741.1(ZBTB46):c.1618G>T(p.Asp540Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,609,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 28)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ZBTB46
NM_001369741.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.11

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB46	NM_001369741.1 link	c.1618G>T	p.Asp540Tyr	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.1618G>T	p.Asp540Tyr	missense_variant	Exon 5 of 5	5	NM_001369741.1	ENSP00000245663.3	Q86UZ6
ZBTB46	ENST00000302995.2 link	c.1618G>T	p.Asp540Tyr	missense_variant	Exon 5 of 7	2		ENSP00000303102.2	Q86UZ6
ZBTB46	ENST00000395104.5 link	c.1618G>T	p.Asp540Tyr	missense_variant	Exon 4 of 4	2		ENSP00000378536.1	Q86UZ6

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000892

AC:

AN:

1457234

Hom.:

Cov.:

AF XY:

0.00000965

AC XY:

AN XY:

725132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151962

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74210

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.000329

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1618G>T (p.D540Y) alteration is located in exon 5 (coding exon 4) of the ZBTB46 gene. This alteration results from a G to T substitution at nucleotide position 1618, causing the aspartic acid (D) at amino acid position 540 to be replaced by a tyrosine (Y). 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

0.28

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;T;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.66

.;.;T

M_CAP

Uncertain

0.089

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.69

N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.026

D;D;D

Sift4G

Benign

0.18

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.51

MutPred

0.34

Gain of phosphorylation at D540 (P = 0.0135);Gain of phosphorylation at D540 (P = 0.0135);Gain of phosphorylation at D540 (P = 0.0135);

MVP

0.068

MPC

0.44

ClinPred

0.93

GERP RS

4.0

Varity_R

0.22

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

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