Genetic Variant ZNF490:p.Lys253Asn (chr19-12581316-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_020714.3(ZNF490):c.759G>C(p.Lys253Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,884 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00043 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

ZNF490
NM_020714.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -8.82

Variant links:

Genes affected

ZNF490 (HGNC:23705): (zinc finger protein 490) Predicted to enable DNA-binding transcription factor 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]

ZNF490 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004051447).

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF490	NM_020714.3 link	c.759G>C	p.Lys253Asn	missense_variant	Exon 5 of 5	ENST00000311437.11	NP_065765.1	Q9ULM2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF490	ENST00000311437.11 link	c.759G>C	p.Lys253Asn	missense_variant	Exon 5 of 5	1	NM_020714.3	ENSP00000311521.6	Q9ULM2
ZNF490	ENST00000414906.5 link	n.*681G>C		non_coding_transcript_exon_variant	Exon 6 of 6	3		ENSP00000402719.1	F8WDW6
ZNF490	ENST00000414906.5 link	n.*681G>C		3_prime_UTR_variant	Exon 6 of 6	3		ENSP00000402719.1	F8WDW6
ZNF490	ENST00000440366.1 link	c.*207G>C		downstream_gene_variant		4		ENSP00000404112.1	C9JID3

Frequencies

GnomAD3 genomes

AF:

0.000428

AC:

AN:

151902

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000416

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

251344

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000217

AC:

317

AN:

1461864

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000267

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000428

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.000457

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000245

Hom.:

Bravo

AF:

0.000574

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.759G>C (p.K253N) alteration is located in exon 5 (coding exon 5) of the ZNF490 gene. This alteration results from a G to C substitution at nucleotide position 759, causing the lysine (K) at amino acid position 253 to be replaced by an asparagine (N). 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

0.47

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.80

CADD

Benign

5.0

DANN

Benign

0.96

DEOGEN2

Benign

0.14

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.00033

LIST_S2

Benign

0.13

M_CAP

Benign

0.0012

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.57

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.027

Sift

Benign

0.27

Sift4G

Benign

0.18

Polyphen

0.74

Vest4

0.074

MutPred

0.40

Loss of methylation at K253 (P = 6e-04);

MVP

0.076

MPC

0.89

ClinPred

0.12

GERP RS

-0.24

Varity_R

0.13

gMVP

0.018

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