Genetic Variant ZNF483:p.Cys161Ser (chr9-111530944-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_133464.5(ZNF483):c.482G>C(p.Cys161Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 27)

Exomes 𝑓: 0.0000022 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZNF483
NM_133464.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.205

Publications

0 publications found

Variant links:

Genes affected

ZNF483 (HGNC:23384): (zinc finger protein 483) 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]

ZNF483 links:

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ACMG classification

Classification was made for transcript

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=0.047362357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF483	NM_133464.5 link	c.482G>C	p.Cys161Ser	missense_variant	Exon 3 of 6	ENST00000309235.6	NP_597721.2	Q8TF39-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF483	ENST00000309235.6 link	c.482G>C	p.Cys161Ser	missense_variant	Exon 3 of 6	1	NM_133464.5	ENSP00000311679.5	Q8TF39-1
ZNF483	ENST00000355824.7 link	c.482G>C	p.Cys161Ser	missense_variant	Exon 3 of 6	1		ENSP00000438048.1	Q6P088
ZNF483	ENST00000358151.8 link	c.482G>C	p.Cys161Ser	missense_variant	Exon 3 of 6	2		ENSP00000350871.4	Q8TF39-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000216

AC:

AN:

1390200

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692266

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32080

American (AMR)

AF:

0.00

AC:

AN:

42444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23890

East Asian (EAS)

AF:

0.00

AC:

AN:

37424

South Asian (SAS)

AF:

0.00

AC:

AN:

79254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48694

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5476

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1064750

Other (OTH)

AF:

0.00

AC:

AN:

56188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.482G>C (p.C161S) alteration is located in exon 3 (coding exon 2) of the ZNF483 gene. This alteration results from a G to C substitution at nucleotide position 482, causing the cysteine (C) at amino acid position 161 to be replaced by a serine (S). 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

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.99

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.0061

.;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0023

LIST_S2

Benign

0.29

T;T;T

M_CAP

Benign

0.0024

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.40

N;.;N

PhyloP100

-0.20

PrimateAI

Benign

0.25

PROVEAN

Benign

0.16

N;N;N

REVEL

Benign

0.019

Sift

Benign

0.67

T;T;T

Sift4G

Benign

0.46

T;T;T

Polyphen

0.0

.;B;B

Vest4

0.14

MutPred

0.25

Gain of phosphorylation at C161 (P = 0.0511);Gain of phosphorylation at C161 (P = 0.0511);Gain of phosphorylation at C161 (P = 0.0511);

MVP

0.061

MPC

0.68

ClinPred

0.022

GERP RS

-2.0

Varity_R

0.030

gMVP

0.081

Mutation Taster

=100/0

polymorphism

(source)

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

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9-111530944-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over