Genetic Variant ZNF493:p.Ser78Arg (chr19-21405837-T-G) – 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_001076678.3(ZNF493):c.234T>G(p.Ser78Arg) 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. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S78I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZNF493
NM_001076678.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.39

Publications

0 publications found

Variant links:

Genes affected

ZNF493 (HGNC:23708): (zinc finger protein 493) Predicted to enable DNA-binding transcription activator 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]

ZNF493 links:

ENSG00000269237 (HGNC:):

ENSG00000269237 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=0.057894975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF493	NM_001076678.3 link	c.234T>G	p.Ser78Arg	missense_variant	Exon 3 of 4	ENST00000392288.7	NP_001070146.1	Q6ZR52-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF493	ENST00000392288.7 link	c.234T>G	p.Ser78Arg	missense_variant	Exon 3 of 4	1	NM_001076678.3	ENSP00000376110.2		Q6ZR52-2
ENSG00000269237	ENST00000600810.1 link	n.177T>G		non_coding_transcript_exon_variant	Exon 2 of 5	3		ENSP00000473166.1		M0R3E3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000210

AC:

AN:

1431012

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

711930

show subpopulations

African (AFR)

AF:

0.0000617

AC:

AN:

32406

American (AMR)

AF:

0.00

AC:

AN:

43082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24866

East Asian (EAS)

AF:

0.00

AC:

AN:

37298

South Asian (SAS)

AF:

0.00

AC:

AN:

84870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50768

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

9.14e-7

AC:

AN:

1093814

Other (OTH)

AF:

0.00

AC:

AN:

58314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 07, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.234T>G (p.S78R) alteration is located in exon 3 (coding exon 3) of the ZNF493 gene. This alteration results from a T to G substitution at nucleotide position 234, causing the serine (S) at amino acid position 78 to be replaced by an arginine (R). 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

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

1.3

(source)

DANN

Benign

0.66

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0013

LIST_S2

Benign

0.28

T;T;T;T

M_CAP

Benign

0.00091

MetaRNN

Benign

0.058

T;T;T;T

MetaSVM

Benign

-0.99

PhyloP100

-1.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.17

.;N;.;N

REVEL

Benign

0.016

Sift

Benign

0.32

.;T;.;D

Sift4G

Benign

0.082

T;T;T;D

Polyphen

0.96

.;D;.;.

Vest4

0.11

MutPred

0.30

.;Loss of ubiquitination at K75 (P = 0.0347);Loss of ubiquitination at K75 (P = 0.0347);.;

MVP

0.072

MPC

0.018

ClinPred

0.12

GERP RS

-2.3

gMVP

0.011

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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19-21405837-T-G

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