16-4752476-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_021646.4(ZNF500):​c.1343G>A​(p.Arg448Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,545,228 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R448W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 34)
Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

ZNF500
NM_021646.4 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.808

Publications

1 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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.05638653).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF500NM_021646.4 linkc.1343G>A p.Arg448Gln missense_variant Exon 6 of 6 ENST00000219478.11 NP_067678.1 O60304-1
ZNF500XM_005255243.5 linkc.992G>A p.Arg331Gln missense_variant Exon 5 of 5 XP_005255300.1
ZNF500NM_001303450.2 linkc.1297+46G>A intron_variant Intron 6 of 6 NP_001290379.1 O60304-2
ZNF500XM_011522453.3 linkc.1297+46G>A intron_variant Intron 6 of 6 XP_011520755.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF500ENST00000219478.11 linkc.1343G>A p.Arg448Gln missense_variant Exon 6 of 6 2 NM_021646.4 ENSP00000219478.5 O60304-1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
151992
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000387
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.000480
GnomAD2 exomes
AF:
0.000113
AC:
17
AN:
149898
AF XY:
0.000111
show subpopulations
Gnomad AFR exome
AF:
0.000135
Gnomad AMR exome
AF:
0.0000796
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000870
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000195
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000135
AC:
188
AN:
1393118
Hom.:
0
Cov.:
32
AF XY:
0.000132
AC XY:
91
AN XY:
688322
show subpopulations
African (AFR)
AF:
0.0000629
AC:
2
AN:
31774
American (AMR)
AF:
0.0000552
AC:
2
AN:
36204
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25266
East Asian (EAS)
AF:
0.000472
AC:
17
AN:
36028
South Asian (SAS)
AF:
0.0000125
AC:
1
AN:
79842
European-Finnish (FIN)
AF:
0.000184
AC:
7
AN:
38024
Middle Eastern (MID)
AF:
0.000357
AC:
2
AN:
5608
European-Non Finnish (NFE)
AF:
0.000138
AC:
149
AN:
1082258
Other (OTH)
AF:
0.000138
AC:
8
AN:
58114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
14
28
43
57
71
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<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:
0.000151
AC:
23
AN:
152110
Hom.:
0
Cov.:
34
AF XY:
0.000121
AC XY:
9
AN XY:
74374
show subpopulations
African (AFR)
AF:
0.0000723
AC:
3
AN:
41492
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000388
AC:
2
AN:
5158
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
0.000283
AC:
3
AN:
10600
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.000206
AC:
14
AN:
67968
Other (OTH)
AF:
0.000475
AC:
1
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000106
Hom.:
0
Bravo
AF:
0.0000982
ExAC
AF:
0.0000623
AC:
7

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 23, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1343G>A (p.R448Q) alteration is located in exon 6 (coding exon 5) of the ZNF500 gene. This alteration results from a G to A substitution at nucleotide position 1343, causing the arginine (R) at amino acid position 448 to be replaced by a glutamine (Q). 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
0.73
BayesDel_addAF
Benign
-0.47
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
21
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.051
T
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.75
T
M_CAP
Benign
0.0039
T
MetaRNN
Benign
0.056
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.36
N
PhyloP100
-0.81
PrimateAI
Uncertain
0.64
T
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.088
Sift
Benign
0.045
D
Sift4G
Benign
0.33
T
Polyphen
0.93
P
Vest4
0.053
MVP
0.20
MPC
0.29
ClinPred
0.062
T
GERP RS
2.1
PromoterAI
0.014
Neutral
Varity_R
0.14
gMVP
0.11
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs552222304; hg19: chr16-4802477; API