chr17-11984133-T-C

Position:

• chr17-11984133-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001303281.2(ZNF18):​c.731A>G​(p.Tyr244Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF18 NM_001303281.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.29

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF18	NM_001303281.2	c.731A>G	p.Tyr244Cys	missense_variant	5/7	ENST00000580306.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF18	ENST00000580306.7	c.731A>G	p.Tyr244Cys	missense_variant	5/7	2	NM_001303281.2	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461372 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727036

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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 08, 2021

The c.731A>G (p.Y244C) alteration is located in exon 7 (coding exon 4) of the ZNF18 gene. This alteration results from a A to G substitution at nucleotide position 731, causing the tyrosine (Y) at amino acid position 244 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	0.68
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Benign	0.16	T;T;T;.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	.;T;.;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Pathogenic	0.81	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;L;L;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.0	.;.;D;D;.
REVEL	Benign	0.25
Sift	Benign	0.061	.;.;T;T;.
Sift4G	Benign	0.086	T;T;T;T;.
Polyphen		1.0	D;D;D;D;.
Vest4		0.82
MutPred		0.79		Loss of phosphorylation at Y244 (P = 0.0502);Loss of phosphorylation at Y244 (P = 0.0502);Loss of phosphorylation at Y244 (P = 0.0502);Loss of phosphorylation at Y244 (P = 0.0502);.;
MVP		0.35
MPC		0.80
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.26
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs749416733; hg19: chr17-11887450;