dbSNP rs552222304: ZNF500:p.Arg448Leu (chr16-4752476-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_021646.4(ZNF500):c.1343G>T(p.Arg448Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R448Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

ZNF500
NM_021646.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.808

Publications

0 publications found

Variant links:

Genes affected

ZNF500 (HGNC:23716): (zinc finger protein 500) 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. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNF500 links:

ENSG00000266994 (HGNC:):

ENSG00000266994 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39543444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF500	NM_021646.4 link	c.1343G>T	p.Arg448Leu	missense_variant	Exon 6 of 6	ENST00000219478.11	NP_067678.1	O60304-1
ZNF500	XM_005255243.5 link	c.992G>T	p.Arg331Leu	missense_variant	Exon 5 of 5		XP_005255300.1
ZNF500	NM_001303450.2 link	c.1297+46G>T		intron_variant	Intron 6 of 6		NP_001290379.1	O60304-2
ZNF500	XM_011522453.3 link	c.1297+46G>T		intron_variant	Intron 6 of 6		XP_011520755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF500	ENST00000219478.11 link	c.1343G>T	p.Arg448Leu	missense_variant	Exon 6 of 6	2	NM_021646.4	ENSP00000219478.5		O60304-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1393118

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688322

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31774

American (AMR)

AF:

0.00

AC:

AN:

36204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25266

East Asian (EAS)

AF:

0.00

AC:

AN:

36028

South Asian (SAS)

AF:

0.00

AC:

AN:

79842

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38024

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5608

European-Non Finnish (NFE)

AF:

9.24e-7

AC:

AN:

1082258

Other (OTH)

AF:

0.00

AC:

AN:

58114

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

-0.042

Eigen_PC

Benign

-0.16

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.75

M_CAP

Benign

0.033

MetaRNN

Benign

0.40

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

PhyloP100

-0.81

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.1

REVEL

Benign

0.17

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.036

Polyphen

1.0

Vest4

0.15

MutPred

0.71

Loss of MoRF binding (P = 0.0266);

MVP

0.26

MPC

0.30

ClinPred

0.99

GERP RS

2.1

PromoterAI

0.016

Neutral

(source)

Varity_R

0.44

gMVP

0.23

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over