Variant chr19-8812050-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144693.3(ZNF558):c.440G>A(p.Arg147His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,585,238 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ZNF558
NM_144693.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.543

Variant links:

Genes affected

ZNF558 (HGNC:26422): (zinc finger protein 558) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF558 links:

ZNF558 (HGNC:):

ZNF558 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.03133914).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF558	NM_144693.3 linkuse as main transcript	c.440G>A	p.Arg147His	missense_variant	10/10	ENST00000601372.6	NP_653294.1	Q96NG5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZNF558	ENST00000601372.6 linkuse as main transcript	c.440G>A	p.Arg147His	missense_variant	10/10	2	NM_144693.3	ENSP00000471277.1	Q96NG5-1
ZNF558	ENST00000301475.1 linkuse as main transcript	c.440G>A	p.Arg147His	missense_variant	6/6	1		ENSP00000301475.1	Q96NG5-1
ZNF558	ENST00000597304.5 linkuse as main transcript	n.1500G>A		non_coding_transcript_exon_variant	8/8	5

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000805

AC:

AN:

223472

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

120486

show subpopulations

Gnomad AFR exome

AF:

0.000322

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000247

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000680

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000117

AC:

168

AN:

1433084

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

709784

show subpopulations

Gnomad4 AFR exome

AF:

0.000215

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000413

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000136

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000133

Gnomad4 OTH exome

AF:

0.0000338

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000647

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.440G>A (p.R147H) alteration is located in exon 6 (coding exon 6) of the ZNF558 gene. This alteration results from a G to A substitution at nucleotide position 440, causing the arginine (R) at amino acid position 147 to be replaced by a histidine (H). 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

0.095

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.80

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0088

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.00050

LIST_S2

Benign

0.78

.;T

M_CAP

Benign

0.0017

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.3

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.68

.;N

REVEL

Benign

0.044

Sift

Benign

0.31

.;T

Sift4G

Benign

0.078

T;T

Polyphen

0.0010

B;B

Vest4

0.012

MVP

0.24

MPC

0.25

ClinPred

0.042

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.12

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