17-11978254-A-C

Position:

• chr17-11978254-A-C

Variant summary

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

The NM_001303281.2(ZNF18):​c.1353T>G​(p.Phe451Leu) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF18 NM_001303281.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.93

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 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=0.031080067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF18	NM_001303281.2	c.1353T>G	p.Phe451Leu	missense_variant	7/7	ENST00000580306.7	NP_001290210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF18	ENST00000580306.7	c.1353T>G	p.Phe451Leu	missense_variant	7/7	2	NM_001303281.2	ENSP00000463471	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 05, 2023

The c.1353T>G (p.F451L) alteration is located in exon 9 (coding exon 6) of the ZNF18 gene. This alteration results from a T to G substitution at nucleotide position 1353, causing the phenylalanine (F) at amino acid position 451 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	0.92
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.10
DANN	Benign	0.70
DEOGEN2	Benign	0.079	T;T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.45	.;T;.;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.031	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	2.4	.;.;N;.
REVEL	Benign	0.11
Sift	Benign	1.0	.;.;T;.
Sift4G	Benign	0.96	T;T;T;T
Polyphen		0.0030	B;B;B;B
Vest4		0.12
MutPred		0.50		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;
MVP		0.099
MPC		0.21
ClinPred		0.085	T
GERP RS		-11
Varity_R		0.041
gMVP		0.24

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: chr17-11881571;