19-58084729-C-T

Position:

• chr19-58084729-C-T

Variant summary

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

The ENST00000601144.6(ZSCAN18):​c.1489G>A​(p.Val497Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000799 in 1,376,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.0000080 (0 hom.)
• Consequence: ZSCAN18 ENST00000601144.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.735

Genes affected

ZSCAN18 (HGNC:21037): (zinc finger and SCAN domain containing 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]

ZSCAN18 (HGNC:):

ZNF135 (HGNC:12919): (zinc finger protein 135) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in cytoskeleton organization and regulation of cell morphogenesis. Predicted to be active 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=0.08161947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZSCAN18	NM_001145543.2	c.1489G>A	p.Val497Met	missense_variant	7/7	ENST00000601144.6	NP_001139015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZSCAN18	ENST00000601144.6	c.1489G>A	p.Val497Met	missense_variant	7/7	1	NM_001145543.2	ENSP00000468934.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000799 AC: 11 AN: 1376976 Hom.: 0 Cov.: 30 AF XY: 0.0000103 AC XY: 7 AN XY: 679588

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: 0.0000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.1657G>A (p.V553M) alteration is located in exon 7 (coding exon 7) of the ZSCAN18 gene. This alteration results from a G to A substitution at nucleotide position 1657, causing the valine (V) at amino acid position 553 to be replaced by a methionine (M). 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	0.18
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.17
DANN	Benign	0.78
DEOGEN2	Benign	0.0089	T;T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0095	N
LIST_S2	Benign	0.45	T;.;T;T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	.;L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.0	.;N;.;N;.
REVEL	Benign	0.022
Sift	Benign	0.47	.;T;.;T;.
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.019	.;B;B;.;.
Vest4		0.064, 0.11, 0.11, 0.15
MutPred		0.46		.;Loss of glycosylation at S496 (P = 0.043);Loss of glycosylation at S496 (P = 0.043);.;.;
MVP		0.20
MPC		0.061
ClinPred		0.044	T
GERP RS		-6.0
Varity_R		0.026
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs1434727763; hg19: chr19-58596096; COSMIC: COSV53734397; COSMIC: COSV53734397;