Genetic Variant ZBTB32:p.Pro134Thr (chr19-35715026-C-A) – 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_014383.3(ZBTB32):c.400C>A(p.Pro134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,612,378 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 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ZBTB32
NM_014383.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.292

Variant links:

Genes affected

ZBTB32 (HGNC:16763): (zinc finger and BTB domain containing 32) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific; identical protein binding activity; and sequence-specific double-stranded DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZBTB32 links:

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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=0.0074026883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB32	NM_014383.3 link	c.400C>A	p.Pro134Thr	missense_variant	Exon 3 of 7	ENST00000392197.7	NP_055198.1	Q9Y2Y4
ZBTB32	NM_001316902.2 link	c.6-437C>A		intron_variant	Intron 2 of 6		NP_001303831.1	Q9Y2Y4
ZBTB32	NM_001316903.2 link	c.-86-437C>A		intron_variant	Intron 2 of 5		NP_001303832.1	Q9Y2Y4
ZBTB32	XM_017026591.2 link	c.6-437C>A		intron_variant	Intron 2 of 5		XP_016882080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZBTB32	ENST00000392197.7 link	c.400C>A	p.Pro134Thr	missense_variant	Exon 3 of 7	5	NM_014383.3	ENSP00000376035.1	Q9Y2Y4
ZBTB32	ENST00000262630.7 link	c.400C>A	p.Pro134Thr	missense_variant	Exon 2 of 6	1		ENSP00000262630.3	Q9Y2Y4
ZBTB32	ENST00000481182.1 link	n.400C>A		non_coding_transcript_exon_variant	Exon 2 of 4	1		ENSP00000433657.1	A0A0C4DGF1
ZBTB32	ENST00000426659.6 link	c.-86-437C>A		intron_variant	Intron 2 of 5	3		ENSP00000466524.1	K7EMJ1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000250

AC:

AN:

247534

Hom.:

AF XY:

0.000253

AC XY:

AN XY:

134172

show subpopulations

Gnomad AFR exome

AF:

0.0000626

Gnomad AMR exome

AF:

0.0000293

Gnomad ASJ exome

AF:

0.00356

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000180

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.000186

AC:

272

AN:

1460210

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

145

AN XY:

726508

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00388

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000112

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000377

Hom.:

Bravo

AF:

0.000140

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000222

AC:

EpiCase

AF:

0.000273

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

Apr 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.400C>A (p.P134T) alteration is located in exon 2 (coding exon 1) of the ZBTB32 gene. This alteration results from a C to A substitution at nucleotide position 400, causing the proline (P) at amino acid position 134 to be replaced by a threonine (T). 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

0.10

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.64

CADD

Benign

5.3

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

T;T

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.62

.;T

M_CAP

Benign

0.0084

MetaRNN

Benign

0.0074

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.8

L;L

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.84

N;N

REVEL

Benign

0.025

Sift

Benign

0.041

D;D

Sift4G

Benign

0.39

T;T

Polyphen

0.42

B;B

Vest4

0.086

MVP

0.36

MPC

0.32

ClinPred

0.015

GERP RS

3.0

Varity_R

0.043

gMVP

0.17

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