19-37127217-C-T

Variant names:

• chr19-37127217-C-T
• rs766427235
• NM_144689.5:c.226C>T

Variant summary

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

The NM_144689.5(ZNF420):​c.226C>T​(p.Leu76Phe) 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. 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: -1.25

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=0.04608187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF420	NM_144689.5	c.226C>T	p.Leu76Phe	missense_variant	Exon 5 of 5	ENST00000337995.4	NP_653290.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF420	ENST00000337995.4	c.226C>T	p.Leu76Phe	missense_variant	Exon 5 of 5	1	NM_144689.5	ENSP00000338770.2
ENSG00000267360	ENST00000588873.1	c.253+28648G>A		intron_variant	Intron 3 of 3	5		ENSP00000465212.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245902 Hom.: 0 AF XY: 0.00000752 AC XY: 1 AN XY: 132892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.226C>T (p.L76F) alteration is located in exon 5 (coding exon 3) of the ZNF420 gene. This alteration results from a C to T substitution at nucleotide position 226, causing the leucine (L) at amino acid position 76 to be replaced by a phenylalanine (F). 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	0.080
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	1.4
DANN	Benign	0.28
DEOGEN2	Benign	0.034	T;.;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.56	T;T;T;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.046	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	.;.;L;.;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.46	.;.;N;.;N
REVEL	Benign	0.030
Sift	Benign	0.52	.;.;T;.;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.0010	.;.;.;.;B
Vest4		0.078, 0.047
MutPred		0.21		.;Loss of stability (P = 0.1139);Loss of stability (P = 0.1139);Loss of stability (P = 0.1139);Loss of stability (P = 0.1139);
MVP		0.11
MPC		0.78
ClinPred		0.0083	T
GERP RS		-1.7
Varity_R		0.038
gMVP		0.029

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: rs766427235; hg19: chr19-37618119;