19-58084884-C-T

Position:

• chr19-58084884-C-T

Variant summary

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

The ENST00000601144.6(ZSCAN18):​c.1334G>A​(p.Gly445Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,444,598 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: 0.0000028 (0 hom.)
• Consequence: ZSCAN18 ENST00000601144.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.43

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 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=0.06470233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZSCAN18	NM_001145543.2	c.1334G>A	p.Gly445Asp	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.1334G>A	p.Gly445Asp	missense_variant	7/7	1	NM_001145543.2	ENSP00000468934.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444598 Hom.: 0 Cov.: 30 AF XY: 0.00000418 AC XY: 3 AN XY: 717476

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000512

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

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

Sep 16, 2021

The c.1502G>A (p.G501D) 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 1502, causing the glycine (G) at amino acid position 501 to be replaced by an aspartic acid (D). 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	0.33
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0031	T;T;T;.;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.0072	N
LIST_S2	Benign	0.67	T;.;T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.065	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.23	.;N;N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	.;N;.;N;.
REVEL	Benign	0.036
Sift	Benign	0.67	.;T;.;T;.
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.061	.;B;B;.;.
Vest4		0.15, 0.18, 0.19
MutPred		0.50		.;Gain of solvent accessibility (P = 0.039);Gain of solvent accessibility (P = 0.039);.;.;
MVP		0.15
MPC		0.078
ClinPred		0.067	T
GERP RS		0.69
Varity_R		0.043
gMVP		0.17

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: rs2074231345; hg19: chr19-58596251; COSMIC: COSV53736691; COSMIC: COSV53736691;