NM_001145543.2:c.1456G>T

Variant names:

• chr19-58084762-C-A
• rs763391279
• NM_001145543.2:c.1456G>T

Variant summary

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

The NM_001145543.2(ZSCAN18):​c.1456G>T​(p.Ala486Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000955 in 1,570,070 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000099 (0 hom.)
• Consequence: ZSCAN18 NM_001145543.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.395

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 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=0.050448895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSCAN18	NM_001145543.2	c.1456G>T	p.Ala486Ser	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.1456G>T	p.Ala486Ser	missense_variant	Exon 7 of 7	1	NM_001145543.2	ENSP00000468934.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 3 AN: 188314 Hom.: 0 AF XY: 0.0000192 AC XY: 2 AN XY: 104062

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: 0.0000351

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000987 AC: 14 AN: 1417882 Hom.: 0 Cov.: 30 AF XY: 0.00000710 AC XY: 5 AN XY: 703896

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: 0.0000127

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74340

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1624G>T (p.A542S) alteration is located in exon 7 (coding exon 7) of the ZSCAN18 gene. This alteration results from a G to T substitution at nucleotide position 1624, causing the alanine (A) at amino acid position 542 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.47	T;.;T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.050	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.56	.;N;N;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.10	.;N;.;N;.
REVEL	Benign	0.0040
Sift	Benign	0.76	.;T;.;T;.
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.010	.;B;B;.;.
Vest4		0.046, 0.10, 0.097, 0.12
MutPred		0.28		.;Gain of phosphorylation at A486 (P = 0.0067);Gain of phosphorylation at A486 (P = 0.0067);.;.;
MVP		0.13
MPC		0.057
ClinPred		0.027	T
GERP RS		-0.97
Varity_R		0.045
gMVP		0.12

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: rs763391279; hg19: chr19-58596129;