19-57677984-A-C

Variant names:

• chr19-57677984-A-C
• rs1425786501
• NM_152677.4:c.467A>C

Variant summary

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

The NM_152677.4(ZSCAN4):​c.467A>C​(p.His156Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000014 (0 hom.)
• Consequence: ZSCAN4 NM_152677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.143

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25963926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSCAN4	NM_152677.4	c.467A>C	p.His156Pro	missense_variant	Exon 4 of 5	ENST00000318203.9	NP_689890.1
ZSCAN4	NM_001384833.1	c.467A>C	p.His156Pro	missense_variant	Exon 6 of 7		NP_001371762.1
ZSCAN4	XM_017026458.1	c.467A>C	p.His156Pro	missense_variant	Exon 4 of 5		XP_016881947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSCAN4	ENST00000318203.9	c.467A>C	p.His156Pro	missense_variant	Exon 4 of 5	2	NM_152677.4	ENSP00000321963.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449898 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721048

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.0000239

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.467A>C (p.H156P) alteration is located in exon 4 (coding exon 2) of the ZSCAN4 gene. This alteration results from a A to C substitution at nucleotide position 467, causing the histidine (H) at amino acid position 156 to be replaced by a proline (P). 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	0.92
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.064	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.48	.;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Benign	0.078
Sift	Benign	0.090	T;.
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;D
Vest4		0.34
MutPred		0.52		Gain of disorder (P = 0.0512);Gain of disorder (P = 0.0512);
MVP		0.13
MPC		0.48
ClinPred		0.71	D
GERP RS		2.1
Varity_R		0.43
gMVP		0.065

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: rs1425786501; hg19: chr19-58189352;