NM_032494.3:c.491G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032494.3(ZC3H8):c.491G>A(p.Gly164Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,613,464 control chromosomes in the GnomAD database, including 21 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 12 hom. )

Consequence

ZC3H8
NM_032494.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.389

Publications

4 publications found

Variant links:

Genes affected

ZC3H8 (HGNC:30941): (zinc finger CCCH-type containing 8) Enables RNA binding activity. Involved in several processes, including positive regulation of thymocyte apoptotic process; regulation of transcription, DNA-templated; and snRNA transcription. Located in Cajal body; histone locus body; and transcriptionally active chromatin. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

ZC3H8 links:

FBLN7 (HGNC:26740): (fibulin 7) Predicted to enable calcium ion binding activity; heparan sulfate proteoglycan binding activity; and heparin binding activity. Predicted to be involved in cell adhesion. Predicted to act upstream of or within positive regulation of biomineralization. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

FBLN7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003587693).

BP6

Variant 2-112236575-C-T is Benign according to our data. Variant chr2-112236575-C-T is described in ClinVar as Benign. ClinVar VariationId is 786486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00736 (1121/152296) while in subpopulation AFR AF = 0.0256 (1065/41548). AF 95% confidence interval is 0.0244. There are 9 homozygotes in GnomAd4. There are 542 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032494.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H8	NM_032494.3	MANE Select	c.491G>A	p.Gly164Asp	missense	Exon 4 of 9	NP_115883.2	Q8N5P1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZC3H8	ENST00000409573.7	TSL:5 MANE Select	c.491G>A	p.Gly164Asp	missense	Exon 4 of 9	ENSP00000386488.1	Q8N5P1
ZC3H8	ENST00000866700.1		c.491G>A	p.Gly164Asp	missense	Exon 4 of 9	ENSP00000536759.1
ZC3H8	ENST00000866701.1		c.491G>A	p.Gly164Asp	missense	Exon 4 of 8	ENSP00000536760.1

Frequencies

GnomAD3 genomes

AF:

0.00735

AC:

1119

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0257

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

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:

0.00430

GnomAD2 exomes

AF:

0.00172

AC:

427

AN:

248586

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.0235

Gnomad AMR exome

AF:

0.00140

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000886

Gnomad OTH exome

AF:

0.000828

GnomAD4 exome

AF:

0.000672

AC:

982

AN:

1461168

Hom.:

Cov.:

AF XY:

0.000546

AC XY:

397

AN XY:

726872

show subpopulations

African (AFR)

AF:

0.0237

AC:

794

AN:

33438

American (AMR)

AF:

0.00155

AC:

AN:

44570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1111754

Other (OTH)

AF:

0.00143

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00736

AC:

1121

AN:

152296

Hom.:

Cov.:

AF XY:

0.00728

AC XY:

542

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0256

AC:

1065

AN:

41548

American (AMR)

AF:

0.00261

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

106

160

213

266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00279

Hom.:

Bravo

AF:

0.00842

ESP6500AA

AF:

0.0229

AC:

ESP6500EA

AF:

0.000364

AC:

ExAC

AF:

0.00215

AC:

260

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.022

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.39

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.32

REVEL

Benign

0.030

Sift

Benign

0.52

Sift4G

Benign

0.35

Polyphen

0.62

Vest4

0.19

MVP

0.10

MPC

0.29

ClinPred

0.024

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.39

Mutation Taster

=100/0

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over