19-37127217-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144689.5(ZNF420):​c.226C>G​(p.Leu76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L76F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZNF420 NM_144689.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.25
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05600947).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144689.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF420	NM_144689.5	MANE Select	c.226C>G	p.Leu76Val	missense	Exon 5 of 5	NP_653290.2
	ZNF420	NM_001329515.3		c.226C>G	p.Leu76Val	missense	Exon 5 of 6	NP_001316444.1
	ZNF420	NM_001329516.3		c.226C>G	p.Leu76Val	missense	Exon 4 of 5	NP_001316445.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF420	ENST00000337995.4	TSL:1 MANE Select	c.226C>G	p.Leu76Val	missense	Exon 5 of 5	ENSP00000338770.2	Q8TAQ5-1
	ENSG00000267360	ENST00000588873.1	TSL:5	c.253+28648G>C		intron	N/A	ENSP00000465212.1	K7EJK4
	ZNF420	ENST00000876809.1		c.226C>G	p.Leu76Val	missense	Exon 5 of 5	ENSP00000546868.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455138 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723276

African (AFR) AF: 0.00 AC: 0 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 43526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25808

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.00 AC: 0 AN: 85056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108962

Other (OTH) AF: 0.00 AC: 0 AN: 60060

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.63
DANN	Benign	0.59
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.0	L
PhyloP100		-1.3
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.025
Sift	Benign	0.40	T
Sift4G	Benign	0.37	T
Polyphen		0.16	B
Vest4		0.11
MutPred		0.22		Loss of stability (P = 0.1802)
MVP		0.12
MPC		0.57
ClinPred		0.028	T
GERP RS		-1.7
Varity_R		0.034
gMVP		0.026
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs766427235; hg19: chr19-37618119;