Genetic Variant ZNF503:p.His453Arg (chr10-75399332-T-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_032772.6(ZNF503):c.1358A>G(p.His453Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,453,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ZNF503
NM_032772.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.46

Variant links:

Genes affected

ZNF503 (HGNC:23589): (zinc finger protein 503) Predicted to enable metal ion binding activity. Involved in G1 to G0 transition involved in cell differentiation; negative regulation of cell population proliferation; and negative regulation of gene expression. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF503 links:

ENSG00000270087 (HGNC:):

ENSG00000270087 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.269306).

BS2

High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF503	NM_032772.6 link	c.1358A>G	p.His453Arg	missense_variant	Exon 2 of 2	ENST00000372524.5	NP_116161.2	Q96F45-1
ZNF503	NR_120651.2 link	n.812+1773A>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF503	ENST00000372524.5 link	c.1358A>G	p.His453Arg	missense_variant	Exon 2 of 2	1	NM_032772.6	ENSP00000361602.4		Q96F45-1
ENSG00000270087	ENST00000418818.6 link	n.142+1773A>G		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000135

AC:

AN:

222316

Hom.:

AF XY:

0.00000813

AC XY:

AN XY:

122980

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000117

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000586

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1453372

Hom.:

Cov.:

AF XY:

0.00000553

AC XY:

AN XY:

722896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1358A>G (p.H453R) alteration is located in exon 2 (coding exon 2) of the ZNF503 gene. This alteration results from a A to G substitution at nucleotide position 1358, causing the histidine (H) at amino acid position 453 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

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.13

Eigen

Benign

0.16

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.5

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.8

REVEL

Benign

0.21

Sift

Uncertain

0.0010

Sift4G

Benign

0.079

Polyphen

0.61

Vest4

0.38

MutPred

0.12

Gain of phosphorylation at S450 (P = 0.0973);

MVP

0.093

MPC

1.3

ClinPred

0.87

GERP RS

3.3

Varity_R

0.85

gMVP

0.84

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