9-101408327-C-T

Variant summary

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

The NM_003452.4(ZNF189):​c.559C>T​(p.Arg187Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R187H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ZNF189
NM_003452.4 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.638
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]

Genome browser will be placed here

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=0.1072813).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF189NM_003452.4 linkc.559C>T p.Arg187Cys missense_variant Exon 3 of 3 ENST00000339664.7 NP_003443.2 O75820-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF189ENST00000339664.7 linkc.559C>T p.Arg187Cys missense_variant Exon 3 of 3 1 NM_003452.4 ENSP00000342019.2 O75820-1
ZNF189ENST00000374861.7 linkc.517C>T p.Arg173Cys missense_variant Exon 3 of 3 1 ENSP00000363995.3 O75820-2
ZNF189ENST00000259395.4 linkc.433C>T p.Arg145Cys missense_variant Exon 4 of 4 1 ENSP00000259395.4 O75820-4
ZNF189ENST00000615466.1 linkc.*380C>T 3_prime_UTR_variant Exon 4 of 4 3 ENSP00000483461.1 A0A087X0K2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250734
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135560
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461796
Hom.:
0
Cov.:
32
AF XY:
0.0000151
AC XY:
11
AN XY:
727198
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000162
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 14, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.559C>T (p.R187C) alteration is located in exon 3 (coding exon 3) of the ZNF189 gene. This alteration results from a C to T substitution at nucleotide position 559, causing the arginine (R) at amino acid position 187 to be replaced by a cysteine (C). 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
0.72
BayesDel_addAF
Uncertain
0.041
T
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
.;T;.
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.0068
N
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.11
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.0
.;L;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Uncertain
-3.0
D;D;N
REVEL
Benign
0.19
Sift
Benign
0.080
T;T;T
Sift4G
Benign
0.087
T;T;T
Polyphen
0.35
.;B;.
Vest4
0.16
MutPred
0.30
.;Loss of disorder (P = 0.0402);.;
MVP
0.25
MPC
0.33
ClinPred
0.85
D
GERP RS
4.7
Varity_R
0.19
gMVP
0.40

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.

Other links and lift over

dbSNP: rs766896414; hg19: chr9-104170609; COSMIC: COSV52276413; API