19-57676223-A-T

Variant names:

• chr19-57676223-A-T
• rs779514724
• NM_152677.4:c.78A>T

Variant summary

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

The NM_152677.4(ZSCAN4):​c.78A>T​(p.Gln26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 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: 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: -0.289

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 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=0.036104828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSCAN4	NM_152677.4	c.78A>T	p.Gln26His	missense_variant	Exon 3 of 5	ENST00000318203.9	NP_689890.1
ZSCAN4	NM_001384833.1	c.78A>T	p.Gln26His	missense_variant	Exon 5 of 7		NP_001371762.1
ZSCAN4	XM_017026458.1	c.78A>T	p.Gln26His	missense_variant	Exon 3 of 5		XP_016881947.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSCAN4	ENST00000318203.9	c.78A>T	p.Gln26His	missense_variant	Exon 3 of 5	2	NM_152677.4	ENSP00000321963.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251370 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.78A>T (p.Q26H) alteration is located in exon 3 (coding exon 1) of the ZSCAN4 gene. This alteration results from a A to T substitution at nucleotide position 78, causing the glutamine (Q) at amino acid position 26 to be replaced by a histidine (H). 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	Uncertain	0.42
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.9
DANN	Benign	0.81
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.27	.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.036	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.50	N;.
REVEL	Benign	0.021
Sift	Benign	0.13	T;.
Sift4G	Benign	0.49	T;T
Polyphen		0.14	B;B
Vest4		0.058
MutPred		0.14		Gain of catalytic residue at Q26 (P = 0.0229);Gain of catalytic residue at Q26 (P = 0.0229);
MVP		0.067
MPC		0.094
ClinPred		0.071	T
GERP RS		-8.3
Varity_R		0.070
gMVP		0.10

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: rs779514724; hg19: chr19-58187591;