Genetic Variant ZNF558:p.Arg40Pro (chr19-8822004-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144693.3(ZNF558):c.119G>C(p.Arg40Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R40Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZNF558
NM_144693.3 missense, splice_region

Scores

Splicing: ADA: 0.00001940

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.127

Publications

0 publications found

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:

ENSG00000269300 (HGNC:):

ENSG00000269300 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10121289).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144693.3. 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
	ZNF558	NM_144693.3	MANE Select	c.119G>C	p.Arg40Pro	missense splice_region	Exon 6 of 10	NP_653294.1	Q96NG5-1
	ZNF558	NM_001304350.2		c.-656G>C		5_prime_UTR	Exon 1 of 5	NP_001291279.1	Q96NG5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF558	ENST00000601372.6	TSL:2 MANE Select	c.119G>C	p.Arg40Pro	missense splice_region	Exon 6 of 10	ENSP00000471277.1	Q96NG5-1
ZNF558	ENST00000301475.1	TSL:1	c.119G>C	p.Arg40Pro	missense splice_region	Exon 2 of 6	ENSP00000301475.1	Q96NG5-1
ZNF558	ENST00000869419.1		c.119G>C	p.Arg40Pro	missense splice_region	Exon 6 of 10	ENSP00000539478.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461692

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111870

Other (OTH)

AF:

0.0000166

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.3

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.0070

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.000095

M_CAP

Benign

0.0012

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.34

PhyloP100

-0.13

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.42

REVEL

Benign

0.062

Sift

Benign

0.18

Sift4G

Uncertain

0.060

Polyphen

0.0

Vest4

0.17

MutPred

0.52

Gain of sheet (P = 0.0477)

MVP

0.048

MPC

0.29

ClinPred

0.037

GERP RS

-6.5

Varity_R

0.072

gMVP

0.62

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000019

dbscSNV1_RF

Benign

0.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over