dbSNP rs147697502: ZC3H3:p.Gln916His (chr8-143440108-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_015117.3(ZC3H3):c.2748G>C(p.Gln916His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,609,346 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0017 ( 4 hom., cov: 34)

Exomes 𝑓: 0.0018 ( 14 hom. )

Consequence

ZC3H3
NM_015117.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.154

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038880706).

BP6

Variant 8-143440108-C-G is Benign according to our data. Variant chr8-143440108-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2658896.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H3	NM_015117.3 link	c.2748G>C	p.Gln916His	missense_variant	Exon 11 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.2748G>C	p.Gln916His	missense_variant	Exon 11 of 12	1	NM_015117.3	ENSP00000262577.5		Q8IXZ2-1

Frequencies

GnomAD3 genomes

AF:

0.00172

AC:

261

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00465

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00931

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00207

AC:

502

AN:

243040

AF XY:

0.00253

show subpopulations

Gnomad AFR exome

AF:

0.0000652

Gnomad AMR exome

AF:

0.000707

Gnomad ASJ exome

AF:

0.00782

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00127

Gnomad OTH exome

AF:

0.00289

GnomAD4 exome

AF:

0.00182

AC:

2657

AN:

1457156

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1540

AN XY:

724550

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33444

American (AMR)

AF:

0.00138

AC:

AN:

44300

Ashkenazi Jewish (ASJ)

AF:

0.00671

AC:

174

AN:

25928

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39614

South Asian (SAS)

AF:

0.0106

AC:

906

AN:

85440

European-Finnish (FIN)

AF:

0.0000961

AC:

AN:

52008

Middle Eastern (MID)

AF:

0.00401

AC:

AN:

5242

European-Non Finnish (NFE)

AF:

0.00123

AC:

1361

AN:

1110984

Other (OTH)

AF:

0.00204

AC:

123

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

174

348

522

696

870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00172

AC:

262

AN:

152190

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

136

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41528

American (AMR)

AF:

0.00464

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00932

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

67978

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00199

Hom.:

Bravo

AF:

0.00196

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00209

AC:

253

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Oct 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ZC3H3: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.76

CADD

Benign

8.6

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0062

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0039

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.63

PhyloP100

-0.15

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.0

REVEL

Benign

0.048

Sift

Benign

0.35

Sift4G

Benign

0.21

Polyphen

0.0

Vest4

0.12

MutPred

0.11

Gain of catalytic residue at Q916 (P = 0.0465);

MVP

0.043

ClinPred

0.0061

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.25

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs147697502

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