chr19-58084810-C-T

Variant names:

• chr19-58084810-C-T
• rs2074228704
• NM_001145543.2:c.1408G>A

Variant summary

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

The NM_001145543.2(ZSCAN18):​c.1408G>A​(p.Ala470Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,126 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A470E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ZSCAN18 NM_001145543.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.845

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=0.05536881).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSCAN18	NM_001145543.2	c.1408G>A	p.Ala470Thr	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.1408G>A	p.Ala470Thr	missense_variant	Exon 7 of 7	1	NM_001145543.2	ENSP00000468934.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1435126 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 712598

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: 9.06e-7

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

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1576G>A (p.A526T) 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 1576, causing the alanine (A) at amino acid position 526 to be replaced by a threonine (T). 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	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.0
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0090	T;T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.45	T;.;T;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.055	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.94	.;L;L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.32	.;N;.;N;.
REVEL	Benign	0.012
Sift	Benign	0.15	.;T;.;T;.
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.019	.;B;B;.;.
Vest4		0.036, 0.090, 0.093, 0.14
MutPred		0.22		.;Gain of phosphorylation at A470 (P = 0.0522);Gain of phosphorylation at A470 (P = 0.0522);.;.;
MVP		0.12
MPC		0.061
ClinPred		0.037	T
GERP RS		-2.8
Varity_R		0.047
gMVP		0.15

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: rs2074228704; hg19: chr19-58596177;