Genetic Variant ZC3H3:p.Arg802Cys (chr8-143441024-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015117.3(ZC3H3):c.2404C>T(p.Arg802Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,480,642 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. R802H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 35)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ZC3H3
NM_015117.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.96

Publications

0 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]

ZC3H3 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0651432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H3	NM_015117.3 link	c.2404C>T	p.Arg802Cys	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
ZC3H3	ENST00000262577.6 link	c.2404C>T	p.Arg802Cys	missense_variant	Exon 10 of 12	1	NM_015117.3	ENSP00000262577.5		Q8IXZ2-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000332

AC:

AN:

120616

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000849

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000799

Gnomad NFE exome

AF:

0.0000330

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000203

AC:

AN:

1328404

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

654118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26272

American (AMR)

AF:

0.00

AC:

AN:

21492

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20748

East Asian (EAS)

AF:

0.0000316

AC:

AN:

31638

South Asian (SAS)

AF:

0.00

AC:

AN:

67734

European-Finnish (FIN)

AF:

0.000222

AC:

AN:

45020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5332

European-Non Finnish (NFE)

AF:

0.0000133

AC:

AN:

1055526

Other (OTH)

AF:

0.0000366

AC:

AN:

54642

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000419

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2404C>T (p.R802C) alteration is located in exon 10 (coding exon 10) of the ZC3H3 gene. This alteration results from a C to T substitution at nucleotide position 2404, causing the arginine (R) at amino acid position 802 to be replaced by a cysteine (C). 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

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.69

M_CAP

Benign

0.040

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.7

PhyloP100

3.0

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.12

Sift

Uncertain

0.028

Sift4G

Uncertain

0.014

Polyphen

0.0070

Vest4

0.27

MutPred

0.23

Loss of MoRF binding (P = 0.0322);

MVP

0.043

ClinPred

0.43

GERP RS

4.8

Varity_R

0.12

gMVP

0.49

Mutation Taster

=73/27

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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8-143441024-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over