Variant 19-8811729-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_144693.3(ZNF558):c.761A>T(p.His254Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZNF558
NM_144693.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.68

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF558	NM_144693.3 linkuse as main transcript	c.761A>T	p.His254Leu	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.761A>T	p.His254Leu	missense_variant	10/10	2	NM_144693.3	ENSP00000471277.1	Q96NG5-1
ZNF558	ENST00000301475.1 linkuse as main transcript	c.761A>T	p.His254Leu	missense_variant	6/6	1		ENSP00000301475.1	Q96NG5-1
ZNF558	ENST00000597304.5 linkuse as main transcript	n.1821A>T		non_coding_transcript_exon_variant	8/8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

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

Jan 03, 2024

The c.761A>T (p.H254L) alteration is located in exon 6 (coding exon 6) of the ZNF558 gene. This alteration results from a A to T substitution at nucleotide position 761, causing the histidine (H) at amino acid position 254 to be replaced by a leucine (L). 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

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

T;T

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.78

.;T

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-11

.;D

REVEL

Pathogenic

0.80

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.92

MVP

0.96

MPC

0.87

ClinPred

1.0

GERP RS

5.0

Varity_R

0.69

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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