Genetic Variant ZBTB32:p.Ala96Val (chr19-35714913-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_014383.3(ZBTB32):c.287C>T(p.Ala96Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000474 in 1,581,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

ZBTB32
NM_014383.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.48

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:

Genome browser will be placed here

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
ZBTB32	NM_014383.3 link	c.287C>T	p.Ala96Val	missense_variant	Exon 3 of 7	ENST00000392197.7	NP_055198.1	Q9Y2Y4
ZBTB32	NM_001316902.2 link	c.6-550C>T		intron_variant	Intron 2 of 6		NP_001303831.1	Q9Y2Y4
ZBTB32	NM_001316903.2 link	c.-86-550C>T		intron_variant	Intron 2 of 5		NP_001303832.1	Q9Y2Y4
ZBTB32	XM_017026591.2 link	c.6-550C>T		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.287C>T	p.Ala96Val	missense_variant	Exon 3 of 7	5	NM_014383.3	ENSP00000376035.1	Q9Y2Y4
ZBTB32	ENST00000262630.7 link	c.287C>T	p.Ala96Val	missense_variant	Exon 2 of 6	1		ENSP00000262630.3	Q9Y2Y4
ZBTB32	ENST00000481182.1 link	n.287C>T		non_coding_transcript_exon_variant	Exon 2 of 4	1		ENSP00000433657.1	A0A0C4DGF1
ZBTB32	ENST00000426659.6 link	c.-86-550C>T		intron_variant	Intron 2 of 5	3		ENSP00000466524.1	K7EMJ1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000449

AC:

AN:

222692

Hom.:

AF XY:

0.0000501

AC XY:

AN XY:

119756

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000199

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000490

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000497

AC:

AN:

1429328

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

708200

show subpopulations

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:

0.000110

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000548

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ExAC

AF:

0.0000412

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.287C>T (p.A96V) alteration is located in exon 2 (coding exon 1) of the ZBTB32 gene. This alteration results from a C to T substitution at nucleotide position 287, causing the alanine (A) at amino acid position 96 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

Pathogenic

0.57

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.83

.;T

M_CAP

Benign

0.023

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.68

N;N

REVEL

Benign

0.20

Sift

Benign

0.054

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.60

MutPred

0.26

Loss of loop (P = 0.0288);Loss of loop (P = 0.0288);

MVP

0.62

MPC

0.39

ClinPred

0.40

GERP RS

4.8

Varity_R

0.39

gMVP

0.31

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