19-37127227-G-A

Position:

• chr19-37127227-G-A

Variant summary

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

The NM_144689.5(ZNF420):​c.236G>A​(p.Cys79Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF420 NM_144689.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.39

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]

ENSG00000267360 (HGNC:):

ZNF585A (HGNC:26305): (zinc finger protein 585A) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in 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 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=0.04140562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF420	NM_144689.5	c.236G>A	p.Cys79Tyr	missense_variant	5/5	ENST00000337995.4	NP_653290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF420	ENST00000337995.4	c.236G>A	p.Cys79Tyr	missense_variant	5/5	1	NM_144689.5	ENSP00000338770.2
ENSG00000267360	ENST00000588873.1	c.253+28638C>T		intron_variant		5		ENSP00000465212.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Sep 08, 2024

The c.236G>A (p.C79Y) alteration is located in exon 5 (coding exon 3) of the ZNF420 gene. This alteration results from a G to A substitution at nucleotide position 236, causing the cysteine (C) at amino acid position 79 to be replaced by a tyrosine (Y). 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	0.066
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.83
DANN	Benign	0.15
DEOGEN2	Benign	0.046	T;.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.55	T;T;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.041	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.24	.;.;N;.;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.87	.;.;N;.;N
REVEL	Benign	0.033
Sift	Benign	1.0	.;.;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.16	.;.;.;.;B
Vest4		0.12, 0.081
MutPred		0.29		.;Gain of phosphorylation at C79 (P = 0.0273);Gain of phosphorylation at C79 (P = 0.0273);Gain of phosphorylation at C79 (P = 0.0273);Gain of phosphorylation at C79 (P = 0.0273);
MVP		0.092
MPC		0.88
ClinPred		0.068	T
GERP RS		2.7
Varity_R		0.082
gMVP		0.074

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-37618129;