19-58084921-T-C

Variant names:

• chr19-58084921-T-C
• rs769249059
• NM_001145543.2:c.1297A>G

Variant summary

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

The NM_001145543.2(ZSCAN18):​c.1297A>G​(p.Ser433Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,596,454 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S433N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: ZSCAN18 NM_001145543.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.78

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]

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=0.07470268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSCAN18	NM_001145543.2	c.1297A>G	p.Ser433Gly	missense_variant	Exon 7 of 7	ENST00000601144.6	NP_001139015.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSCAN18	ENST00000601144.6	c.1297A>G	p.Ser433Gly	missense_variant	Exon 7 of 7	1	NM_001145543.2	ENSP00000468934.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000120 AC: 26 AN: 216018 Hom.: 0 AF XY: 0.000136 AC XY: 16 AN XY: 117592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000322

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000361

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000192 AC: 277 AN: 1444288 Hom.: 1 Cov.: 30 AF XY: 0.000212 AC XY: 152 AN XY: 717344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000285

Gnomad4 NFE exome AF: 0.000233

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000580 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1465A>G (p.S489G) alteration is located in exon 7 (coding exon 7) of the ZSCAN18 gene. This alteration results from a A to G substitution at nucleotide position 1465, causing the serine (S) at amino acid position 489 to be replaced by a glycine (G). 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	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.5
DANN	Benign	0.82
DEOGEN2	Benign	0.027	T;T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.071	T;.;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.075	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.54	.;N;N;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	.;N;.;N;.
REVEL	Benign	0.028
Sift	Benign	0.12	.;T;.;T;.
Sift4G	Uncertain	0.049	D;D;D;T;D
Polyphen		0.0020	.;B;B;.;.
Vest4		0.070, 0.17, 0.16, 0.17
MutPred		0.56		.;Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;.;
MVP		0.068
MPC		0.060
ClinPred		0.018	T
GERP RS		1.8
Varity_R		0.054
gMVP		0.080

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: rs769249059; hg19: chr19-58596288;