GeneBe

8-143441035-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015117.3(ZC3H3):​c.2393G>A​(p.Arg798His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000579 in 1,486,362 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 35)
Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

ZC3H3
NM_015117.3 missense

Scores

2
9
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.12

Publications

1 publications found
Variant links:
Genes affected
ZC3H3 (HGNC:28972): (zinc finger CCCH-type containing 3) Predicted to enable SMAD binding activity. Involved in regulation of mRNA polyadenylation. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZC3H3NM_015117.3 linkc.2393G>A p.Arg798His missense_variant Exon 10 of 12 ENST00000262577.6 NP_055932.2 Q8IXZ2-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZC3H3ENST00000262577.6 linkc.2393G>A p.Arg798His missense_variant Exon 10 of 12 1 NM_015117.3 ENSP00000262577.5 Q8IXZ2-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152200
Hom.:
0
Cov.:
35
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000251
AC:
3
AN:
119490
AF XY:
0.0000296
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:
0.0000804
Gnomad NFE exome
AF:
0.0000333
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000585
AC:
78
AN:
1334162
Hom.:
0
Cov.:
31
AF XY:
0.0000562
AC XY:
37
AN XY:
658142
show subpopulations
African (AFR)
AF:
0.000152
AC:
4
AN:
26370
American (AMR)
AF:
0.00
AC:
0
AN:
21374
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
21086
East Asian (EAS)
AF:
0.00
AC:
0
AN:
31756
South Asian (SAS)
AF:
0.0000147
AC:
1
AN:
68100
European-Finnish (FIN)
AF:
0.0000221
AC:
1
AN:
45174
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5376
European-Non Finnish (NFE)
AF:
0.0000660
AC:
70
AN:
1059990
Other (OTH)
AF:
0.0000364
AC:
2
AN:
54936
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.477
Heterozygous variant carriers
0
7
14
21
28
35
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000526
AC:
8
AN:
152200
Hom.:
0
Cov.:
35
AF XY:
0.0000672
AC XY:
5
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41464
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
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:
0.000103
AC:
7
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
1
2
2
3
4
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:
0.00
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.00000839
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 13, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2393G>A (p.R798H) alteration is located in exon 10 (coding exon 10) of the ZC3H3 gene. This alteration results from a G to A substitution at nucleotide position 2393, causing the arginine (R) at amino acid position 798 to be replaced by a histidine (H). 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
Uncertain
0.36
BayesDel_addAF
Benign
-0.032
T
BayesDel_noAF
Benign
-0.28
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.016
T
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.88
D
M_CAP
Uncertain
0.27
D
MetaRNN
Uncertain
0.46
T
MetaSVM
Benign
-0.46
T
MutationAssessor
Pathogenic
2.9
M
PhyloP100
2.1
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.24
Sift
Uncertain
0.0090
D
Sift4G
Benign
0.065
T
Polyphen
1.0
D
Vest4
0.48
MVP
0.26
ClinPred
0.68
D
GERP RS
4.8
Varity_R
0.12
gMVP
0.57
Mutation Taster
=80/20
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: rs368841712; hg19: chr8-144523205; COSMIC: COSV108784457; API