9-101408199-A-G

Variant names:

• chr9-101408199-A-G
• NM_003452.4:c.431A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003452.4(ZNF189):​c.431A>G​(p.Glu144Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF189 NM_003452.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.739

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]

ACMG classification

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=0.03190431).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF189	NM_003452.4	c.431A>G	p.Glu144Gly	missense_variant	Exon 3 of 3	ENST00000339664.7	NP_003443.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF189	ENST00000339664.7	c.431A>G	p.Glu144Gly	missense_variant	Exon 3 of 3	1	NM_003452.4	ENSP00000342019.2
ZNF189	ENST00000374861.7	c.389A>G	p.Glu130Gly	missense_variant	Exon 3 of 3	1		ENSP00000363995.3
ZNF189	ENST00000259395.4	c.305A>G	p.Glu102Gly	missense_variant	Exon 4 of 4	1		ENSP00000259395.4
ZNF189	ENST00000615466.1	c.*252A>G		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000483461.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.431A>G (p.E144G) alteration is located in exon 3 (coding exon 3) of the ZNF189 gene. This alteration results from a A to G substitution at nucleotide position 431, causing the glutamic acid (E) at amino acid position 144 to be replaced by a glycine (G). 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	0.088
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.24
DEOGEN2	Benign	0.0050	.;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.029	T;T;T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.3	.;N;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	3.4	N;N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.20
MutPred		0.29		.;Loss of ubiquitination at K149 (P = 0.0219);.;
MVP		0.15
MPC		0.18
ClinPred		0.14	T
GERP RS		4.7
Varity_R		0.053
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-104170481;