Genetic Variant ZBTB46:p.Ala403Val (chr20-63775692-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001369741.1(ZBTB46):c.1208C>T(p.Ala403Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZBTB46
NM_001369741.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.34

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20322496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB46	NM_001369741.1 link	c.1208C>T	p.Ala403Val	missense_variant	Exon 3 of 5	ENST00000245663.9	NP_001356670.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB46	ENST00000245663.9 link	c.1208C>T	p.Ala403Val	missense_variant	Exon 3 of 5	5	NM_001369741.1	ENSP00000245663.3		Q86UZ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1425590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705052

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1208C>T (p.A403V) alteration is located in exon 3 (coding exon 2) of the ZBTB46 gene. This alteration results from a C to T substitution at nucleotide position 1208, causing the alanine (A) at amino acid position 403 to be replaced by a valine (V). 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

0.20

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.027

T;T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.91

.;.;D

M_CAP

Benign

0.0077

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.98

N;N;N

REVEL

Benign

0.090

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.049

B;B;B

Vest4

0.099

MutPred

0.79

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);

MVP

0.068

MPC

0.67

ClinPred

0.53

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.14

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over