4-10443604-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_053042.3(ZNF518B):​c.2725C>A​(p.Arg909Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R909C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

ZNF518B
NM_053042.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

Publications

1 publications found
Variant links:
Genes affected
ZNF518B (HGNC:29365): (zinc finger protein 518B) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription 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]
ZNF518B Gene-Disease associations (from GenCC):
  • schizophrenia
    Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.09966645).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF518BNM_053042.3 linkc.2725C>A p.Arg909Ser missense_variant Exon 3 of 3 ENST00000326756.4 NP_444270.2 Q9C0D4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF518BENST00000326756.4 linkc.2725C>A p.Arg909Ser missense_variant Exon 3 of 3 3 NM_053042.3 ENSP00000317614.3 Q9C0D4

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000359
AC:
9
AN:
250924
AF XY:
0.0000443
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000795
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000540
AC:
79
AN:
1461850
Hom.:
0
Cov.:
31
AF XY:
0.0000578
AC XY:
42
AN XY:
727222
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53402
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000656
AC:
73
AN:
1111986
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.460
Heterozygous variant carriers
0
5
11
16
22
27
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152176
Hom.:
0
Cov.:
33
AF XY:
0.0000942
AC XY:
7
AN XY:
74332
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41440
American (AMR)
AF:
0.00
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000250
AC:
17
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.497
Heterozygous variant carriers
0
2
4
5
7
9
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:
0.0000467
Hom.:
0
Bravo
AF:
0.000102
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 26, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2725C>A (p.R909S) alteration is located in exon 3 (coding exon 1) of the ZNF518B gene. This alteration results from a C to A substitution at nucleotide position 2725, causing the arginine (R) at amino acid position 909 to be replaced by a serine (S). 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
Benign
0.20
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
14
DANN
Benign
0.87
DEOGEN2
Benign
0.0022
T
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.15
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.65
T
M_CAP
Benign
0.0092
T
MetaRNN
Benign
0.10
T
MetaSVM
Benign
-0.80
T
MutationAssessor
Uncertain
2.2
M
PhyloP100
1.0
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.53
N
REVEL
Benign
0.15
Sift
Benign
0.21
T
Sift4G
Benign
0.46
T
Polyphen
0.89
P
Vest4
0.13
MutPred
0.22
Loss of MoRF binding (P = 0.0148);
MVP
0.093
MPC
0.029
ClinPred
0.11
T
GERP RS
6.0
Varity_R
0.22
gMVP
0.26
Mutation Taster
=85/15
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: rs561875461; hg19: chr4-10445228; API