17-11983392-G-A

Variant names:

• chr17-11983392-G-A
• rs1312663563
• NM_001303281.2:c.767C>T

Variant summary

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

The NM_001303281.2(ZNF18):​c.767C>T​(p.Pro256Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,564 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZNF18 NM_001303281.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

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=0.14183801).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF18	NM_001303281.2	c.767C>T	p.Pro256Leu	missense_variant	Exon 6 of 7	ENST00000580306.7	NP_001290210.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF18	ENST00000580306.7	c.767C>T	p.Pro256Leu	missense_variant	Exon 6 of 7	2	NM_001303281.2	ENSP00000463471.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250294 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135360

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461564 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727110

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.767C>T (p.P256L) alteration is located in exon 8 (coding exon 5) of the ZNF18 gene. This alteration results from a C to T substitution at nucleotide position 767, causing the proline (P) at amino acid position 256 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	Benign	0.19
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Benign	0.82
DEOGEN2	Benign	0.21	T;T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.45	.;T;.;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L;L;L;.
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.4	.;.;N;.
REVEL	Benign	0.092
Sift	Uncertain	0.0030	.;.;D;.
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.0080	B;B;B;B
Vest4		0.24
MutPred		0.32		Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);.;
MVP		0.36
MPC		0.19
ClinPred		0.40	T
GERP RS		3.6
Varity_R		0.091
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1312663563; hg19: chr17-11886709;