9-101408328-G-A

Variant summary

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

The ENST00000339664.7(ZNF189):​c.560G>A​(p.Arg187His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,876 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. R187C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ZNF189
ENST00000339664.7 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0850
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=0.07469472).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ZNF189NM_003452.4 linkuse as main transcriptc.560G>A p.Arg187His missense_variant 3/3 ENST00000339664.7 NP_003443.2 O75820-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ZNF189ENST00000339664.7 linkuse as main transcriptc.560G>A p.Arg187His missense_variant 3/31 NM_003452.4 ENSP00000342019.2 O75820-1
ZNF189ENST00000374861.7 linkuse as main transcriptc.518G>A p.Arg173His missense_variant 3/31 ENSP00000363995.3 O75820-2
ZNF189ENST00000259395.4 linkuse as main transcriptc.434G>A p.Arg145His missense_variant 4/41 ENSP00000259395.4 O75820-4
ZNF189ENST00000615466.1 linkuse as main transcriptc.*381G>A 3_prime_UTR_variant 4/43 ENSP00000483461.1 A0A087X0K2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152088
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
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
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250700
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135544
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:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000821
AC:
12
AN:
1461788
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727192
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:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152088
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74278
show subpopulations
Gnomad4 AFR
AF:
0.0000242
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:
0.00000378
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 12, 2022The c.560G>A (p.R187H) alteration is located in exon 3 (coding exon 3) of the ZNF189 gene. This alteration results from a G to A substitution at nucleotide position 560, causing the arginine (R) at amino acid position 187 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
Pathogenic
0.65
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.48
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.037
.;T;.
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.0059
N
LIST_S2
Benign
0.85
D;D;D
M_CAP
Benign
0.0040
T
MetaRNN
Benign
0.075
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.17
.;N;.
MutationTaster
Benign
0.74
D;D;D
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-1.7
N;N;N
REVEL
Benign
0.15
Sift
Benign
0.18
T;T;T
Sift4G
Benign
0.23
T;T;T
Polyphen
0.30
.;B;.
Vest4
0.11
MutPred
0.29
.;Loss of phosphorylation at S189 (P = 0.0679);.;
MVP
0.17
MPC
0.29
ClinPred
0.36
T
GERP RS
4.7
Varity_R
0.097
gMVP
0.34

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: rs954451072; hg19: chr9-104170610; COSMIC: COSV99407313; API