chr19-37128067-G-C

Position:

• chr19-37128067-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144689.5(ZNF420):​c.1076G>C​(p.Gly359Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF420 NM_144689.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.18

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]

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24636033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF420	NM_144689.5	c.1076G>C	p.Gly359Ala	missense_variant	5/5	ENST00000337995.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF420	ENST00000337995.4	c.1076G>C	p.Gly359Ala	missense_variant	5/5	1	NM_144689.5	P1
ZNF420	ENST00000304239.11	c.1076G>C	p.Gly359Ala	missense_variant	5/6	2
ZNF585A	ENST00000587817.5	c.338-12902C>G		intron_variant, NMD_transcript_variant		2
ZNF585A	ENST00000588723.5	n.503-12902C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 15, 2024

The c.1076G>C (p.G359A) alteration is located in exon 5 (coding exon 3) of the ZNF420 gene. This alteration results from a G to C substitution at nucleotide position 1076, causing the glycine (G) at amino acid position 359 to be replaced by an alanine (A). 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	0.54
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.57	.;P
Vest4		0.39
MutPred		0.39		Loss of disorder (P = 0.1205);Loss of disorder (P = 0.1205);
MVP		0.25
MPC		1.0
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.51
gMVP		0.033

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: rs1422313539; hg19: chr19-37618969;