Genetic Variant ZNF12:p.Tyr552His (chr7-6691288-A-G) – 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_016265.4(ZNF12):c.1654T>C(p.Tyr552His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,314 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 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

ZNF12
NM_016265.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.778

Variant links:

Genes affected

ZNF12 (HGNC:12902): (zinc finger protein 12) This gene is a member of the krueppel C2H2-type zinc-finger protein family and encodes a protein with eight C2H2-type zinc fingers and a KRAB domain. This nuclear protein is involved in developmental control of gene expression. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ZNF12 links:

ENSG00000228010 (HGNC:):

ENSG00000228010 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=0.03982863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF12	NM_016265.4 link	c.1654T>C	p.Tyr552His	missense_variant	Exon 5 of 5	ENST00000405858.6	NP_057349.2	P17014-1
ZNF12	NM_006956.3 link	c.1540T>C	p.Tyr514His	missense_variant	Exon 6 of 6		NP_008887.2	P17014-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF12	ENST00000405858.6 link	c.1654T>C	p.Tyr552His	missense_variant	Exon 5 of 5	1	NM_016265.4	ENSP00000385939.1	P17014-1
ZNF12	ENST00000404360.5 link	c.1432T>C	p.Tyr478His	missense_variant	Exon 5 of 5	1		ENSP00000384405.1	P17014-4
ZNF12	ENST00000342651.9 link	c.1540T>C	p.Tyr514His	missense_variant	Exon 6 of 6	2		ENSP00000344745.5	P17014-5
ENSG00000228010	ENST00000366167.2 link	n.136-17013A>G		intron_variant	Intron 2 of 3	4

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151570

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:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000560

AC:

AN:

249960

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461744

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151570

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74006

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000295

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000660

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1654T>C (p.Y552H) alteration is located in exon 5 (coding exon 4) of the ZNF12 gene. This alteration results from a T to C substitution at nucleotide position 1654, causing the tyrosine (Y) at amino acid position 552 to be replaced by a histidine (H). 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

-0.50

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

.;T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.00022

LIST_S2

Benign

0.36

T;T;T

M_CAP

Benign

0.0089

MetaRNN

Benign

0.040

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.4

.;N;.

PrimateAI

Benign

0.45

PROVEAN

Benign

2.0

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.97, 0.97

.;D;D

Vest4

0.30

MutPred

0.24

.;Gain of disorder (P = 0.0399);.;

MVP

0.18

MPC

0.84

ClinPred

0.12

GERP RS

0.031

Varity_R

0.020

gMVP

0.18

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