19-57678855-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152677.4(ZSCAN4):c.1252C>T(p.His418Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,459,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: ZSCAN4 NM_152677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20

Genes affected

ZSCAN4 (HGNC:23709): (zinc finger and SCAN domain containing 4) The ZSCAN4 gene encodes a protein involved in telomere maintenance and with a key role in the critical feature of mouse embryonic stem (ES) cells, namely, defying cellular senescence and maintaining normal karyotype for many cell divisions in culture (Zalzman et al., 2010 [PubMed 20336070]).[supplied by OMIM, May 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZSCAN4	NM_152677.4	c.1252C>T	p.His418Tyr	missense_variant	5/5	ENST00000318203.9
ZSCAN4	NM_001384833.1	c.1252C>T	p.His418Tyr	missense_variant	7/7
ZSCAN4	XM_017026458.1	c.1252C>T	p.His418Tyr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZSCAN4	ENST00000318203.9	c.1252C>T	p.His418Tyr	missense_variant	5/5	2	NM_152677.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1459744 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726054

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: 0.00000990

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

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

Jul 25, 2023

The c.1252C>T (p.H418Y) alteration is located in exon 5 (coding exon 3) of the ZSCAN4 gene. This alteration results from a C to T substitution at nucleotide position 1252, causing the histidine (H) at amino acid position 418 to be replaced by a tyrosine (Y). 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Uncertain	0.45	T;T
Eigen	Benign	0.15
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.0093	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.65	D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.1	D;.
REVEL	Benign	0.16
Sift	Uncertain	0.025	D;.
Sift4G	Benign	0.27	T;T
Polyphen		1.0	D;D
Vest4		0.52
MutPred		0.65		Gain of phosphorylation at H418 (P = 0.0213);Gain of phosphorylation at H418 (P = 0.0213);
MVP		0.072
MPC		0.33
ClinPred		0.82	D
GERP RS		3.4
Varity_R		0.25
gMVP		0.057

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: rs759029463; hg19: chr19-58190223;