Genetic Variant ZNF568:p.Tyr488His (chr19-36997153-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000444991.6(ZNF568):c.1462T>C(p.Tyr488His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ZNF568
ENST00000444991.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.62

Publications

16 publications found

Variant links:

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]

ZNF568 links:

ENSG00000291239 (HGNC:):

ENSG00000291239 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.798

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
ZNF568	NM_001204838.2 link	c.1462T>C	p.Tyr488His	missense_variant	Exon 10 of 10	NP_001191767.1	Q3ZCX4C9JLX5Q96AZ9
ZNF568	NM_001204839.2 link	c.1270T>C	p.Tyr424His	missense_variant	Exon 9 of 9	NP_001191768.1	Q3ZCX4-3Q96AZ9
ZNF568	XM_017026772.2 link	c.1462T>C	p.Tyr488His	missense_variant	Exon 10 of 10	XP_016882261.1	C9JLX5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000291239	ENST00000706165.1 link	c.1462T>C	p.Tyr488His	missense_variant	Exon 12 of 12			ENSP00000516244.1		C9JLX5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151878

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151878

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74164

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41320

American (AMR)

AF:

0.00

AC:

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

3659

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;.;.;.

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.76

T;T;T;D

M_CAP

Benign

0.0089

MetaRNN

Pathogenic

0.80

D;D;D;D

MetaSVM

Benign

-0.85

PhyloP100

7.6

PROVEAN

Uncertain

-4.0

D;D;.;D

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Vest4

0.34, 0.38

MutPred

0.70

Gain of disorder (P = 0.0119);.;Gain of disorder (P = 0.0119);.;

MVP

0.44

ClinPred

0.95

GERP RS

3.9

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over