Genetic Variant ZNF189:p.Phe130Leu (chr9-101408158-C-G) – 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_003452.4(ZNF189):c.390C>G(p.Phe130Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

ZNF189
NM_003452.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.503

Variant links:

Genes affected

ZNF189 (HGNC:12980): (zinc finger protein 189) Kruppel-like zinc finger proteins such as ZNF189 contain a conserved stretch of 7 amino acids that connects a variable number of DNA-binding zinc finger repeats of the cys(2)his(2) (C2H2) type (summarized by Odeberg et al., 1998 [PubMed 9653648]). Approximately 30% of human Kruppel-like zinc finger proteins contain an N-terminal Kruppel-associated box (KRAB) domain. The KRAB domain consists of approximately 75 amino acids that may be subdivided into an A box, which is present in every KRAB domain and is essential for transcriptional repression, and a B box, which is not always present.[supplied by OMIM, May 2010]

ZNF189 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=0.112724096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF189	NM_003452.4 link	c.390C>G	p.Phe130Leu	missense_variant	Exon 3 of 3	ENST00000339664.7	NP_003443.2	O75820-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF189	ENST00000339664.7 link	c.390C>G	p.Phe130Leu	missense_variant	Exon 3 of 3	1	NM_003452.4	ENSP00000342019.2	O75820-1
ZNF189	ENST00000374861.7 link	c.348C>G	p.Phe116Leu	missense_variant	Exon 3 of 3	1		ENSP00000363995.3	O75820-2
ZNF189	ENST00000259395.4 link	c.264C>G	p.Phe88Leu	missense_variant	Exon 4 of 4	1		ENSP00000259395.4	O75820-4
ZNF189	ENST00000615466.1 link	c.*211C>G		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000483461.1	A0A087X0K2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.390C>G (p.F130L) alteration is located in exon 3 (coding exon 3) of the ZNF189 gene. This alteration results from a C to G substitution at nucleotide position 390, causing the phenylalanine (F) at amino acid position 130 to be replaced by a leucine (L). 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

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.047

.;T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.0091

LIST_S2

Benign

0.27

T;T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

3.1

.;M;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.14

T;T;T

Sift4G

Uncertain

0.037

D;D;D

Polyphen

0.0040

.;B;.

Vest4

0.15

MutPred

0.29

.;Gain of catalytic residue at F130 (P = 0.0178);.;

MVP

0.56

MPC

0.069

ClinPred

0.37

GERP RS

1.4

Varity_R

0.078

gMVP

0.13

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