17-11990542-C-G

Position:

• chr17-11990542-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001303281.2(ZNF18):​c.586G>C​(p.Ala196Pro) 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF18 NM_001303281.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.189

Genes affected

ZNF18 (HGNC:12969): (zinc finger protein 18) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.11627579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF18	NM_001303281.2	c.586G>C	p.Ala196Pro	missense_variant	4/7	ENST00000580306.7	NP_001290210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF18	ENST00000580306.7	c.586G>C	p.Ala196Pro	missense_variant	4/7	2	NM_001303281.2	ENSP00000463471.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.586G>C (p.A196P) alteration is located in exon 6 (coding exon 3) of the ZNF18 gene. This alteration results from a G to C substitution at nucleotide position 586, causing the alanine (A) at amino acid position 196 to be replaced by a proline (P). 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	0.22
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.055	T;T;T;.;T
Eigen	Benign	0.039
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.70	.;T;.;T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;M;M;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	.;.;N;N;.
REVEL	Benign	0.071
Sift	Benign	0.26	.;.;T;T;.
Sift4G	Benign	0.23	T;T;T;T;.
Polyphen		0.94	P;P;P;D;.
Vest4		0.32
MutPred		0.22		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);.;
MVP		0.31
MPC		0.27
ClinPred		0.34	T
GERP RS		4.7
Varity_R		0.091
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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

Other links and lift over

dbSNP: rs1597971413; hg19: chr17-11893859;