Genetic Variant ZNF503:p.Ala580Thr (chr10-75398952-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032772.6(ZNF503):c.1738G>A(p.Ala580Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000711 in 1,599,974 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00074 ( 3 hom. )

Consequence

ZNF503
NM_032772.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

Publications

3 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028776348).

BS2

High AC in GnomAd4 at 73 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032772.6. 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
	ZNF503	NM_032772.6	MANE Select	c.1738G>A	p.Ala580Thr	missense	Exon 2 of 2	NP_116161.2
	ZNF503	NR_120651.2		n.812+2153G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF503	ENST00000372524.5	TSL:1 MANE Select	c.1738G>A	p.Ala580Thr	missense	Exon 2 of 2	ENSP00000361602.4	Q96F45-1
	ENSG00000270087	ENST00000418818.6	TSL:3	n.142+2153G>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000474

AC:

104

AN:

219576

AF XY:

0.000486

show subpopulations

Gnomad AFR exome

AF:

0.000454

Gnomad AMR exome

AF:

0.000872

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000582

Gnomad FIN exome

AF:

0.0000714

Gnomad NFE exome

AF:

0.000656

Gnomad OTH exome

AF:

0.000364

GnomAD4 exome

AF:

0.000736

AC:

1065

AN:

1447782

Hom.:

Cov.:

AF XY:

0.000758

AC XY:

546

AN XY:

720074

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33376

American (AMR)

AF:

0.00111

AC:

AN:

43966

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25822

East Asian (EAS)

AF:

0.00

AC:

AN:

39466

South Asian (SAS)

AF:

0.0000468

AC:

AN:

85404

European-Finnish (FIN)

AF:

0.000111

AC:

AN:

45068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.000864

AC:

958

AN:

1108960

Other (OTH)

AF:

0.000750

AC:

AN:

59968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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

AF:

0.000480

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000498

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41448

American (AMR)

AF:

0.00105

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68018

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000440

Hom.:

Bravo

AF:

0.000593

ESP6500AA

AF:

0.000231

AC:

ESP6500EA

AF:

0.000589

AC:

ExAC

AF:

0.000327

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.53

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

Eigen

Benign

-0.10

Eigen_PC

Benign

0.019

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.047

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

2.0

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-2.2

REVEL

Benign

0.055

Sift

Benign

0.037

Sift4G

Benign

0.39

Polyphen

0.12

Vest4

0.075

MVP

0.11

MPC

0.55

ClinPred

0.021

GERP RS

4.6

Varity_R

0.11

gMVP

0.57

Mutation Taster

=98/2

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over