Genetic Variant ZNF420:p.Tyr39Cys (chr19-37091101-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001329517.1(ZNF420):c.-183A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ZNF420
NM_001329517.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.82

Variant links:

Genes affected

ZNF420 (HGNC:20649): (zinc finger protein 420) The protein encoded by this gene is a KRAB-type zinc finger protein that negatively-regulates p53-mediated apoptosis. Under stress conditions, the encoded protein is phosphorylated by ATM and dissociates from p53, which activates p53 and initiates apoptosis. [provided by RefSeq, Jul 2016]

ZNF420 links:

ENSG00000267672 (HGNC:):

ENSG00000267672 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
ZNF420	NM_144689.5 link	c.116A>G	p.Tyr39Cys	missense_variant	Exon 4 of 5	ENST00000337995.4	NP_653290.2	Q8TAQ5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF420	ENST00000337995.4 link	c.116A>G	p.Tyr39Cys	missense_variant	Exon 4 of 5	1	NM_144689.5	ENSP00000338770.2		Q8TAQ5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000423

AC:

AN:

236500

Hom.:

AF XY:

0.00000783

AC XY:

AN XY:

127650

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000918

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.93e-7

AC:

AN:

1442462

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715924

show subpopulations

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:

9.06e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.116A>G (p.Y39C) alteration is located in exon 4 (coding exon 2) of the ZNF420 gene. This alteration results from a A to G substitution at nucleotide position 116, causing the tyrosine (Y) at amino acid position 39 to be replaced by a cysteine (C). 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

Benign

0.33

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

.;.;T;T

Eigen

Benign

-0.098

Eigen_PC

Benign

-0.070

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.14

T;T;T;T

M_CAP

Benign

0.0034

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

.;M;.;M

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.2

.;D;.;D

REVEL

Benign

0.19

Sift

Pathogenic

0.0

.;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.024

.;.;.;B

Vest4

0.78, 0.78

MutPred

0.71

Loss of phosphorylation at Y39 (P = 0.0624);Loss of phosphorylation at Y39 (P = 0.0624);Loss of phosphorylation at Y39 (P = 0.0624);Loss of phosphorylation at Y39 (P = 0.0624);

MVP

0.32

MPC

1.2

ClinPred

0.89

GERP RS

2.2

Varity_R

0.36

gMVP

0.049

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over