19-36950350-C-A

Position:

• chr19-36950350-C-A

Variant summary

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

The NM_198539.4(ZNF568):​c.1197C>A​(p.Phe399Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF568 NM_198539.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.651

Genes affected

ZNF568 (HGNC:25392): (zinc finger protein 568) 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 embryonic placenta morphogenesis and negative regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF568	NM_198539.4	c.1197C>A	p.Phe399Leu	missense_variant	7/7	ENST00000333987.12	NP_940941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF568	ENST00000333987.12	c.1197C>A	p.Phe399Leu	missense_variant	7/7	1	NM_198539.4	ENSP00000334685	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 33

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

Jan 02, 2024

The c.1197C>A (p.F399L) alteration is located in exon 7 (coding exon 5) of the ZNF568 gene. This alteration results from a C to A substitution at nucleotide position 1197, causing the phenylalanine (F) at amino acid position 399 to be replaced by a leucine (L). 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	1.0
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;.;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.67	.;T;T;T;T
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.1	M;.;.;M;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.0	D;D;.;.;.
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D;D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;.;.;D;.
Vest4		0.55
MutPred		0.70		Loss of helix (P = 0.1299);.;.;Loss of helix (P = 0.1299);.;
MVP		0.55
MPC		0.84
ClinPred		0.99	D
GERP RS		0.83
Varity_R		0.71
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: rs76825607; hg19: chr19-37441252;