2-112236575-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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 made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H8	NM_032494.3 link	c.491G>A	p.Gly164Asp	missense_variant	Exon 4 of 9	ENST00000409573.7	NP_115883.2	Q8N5P1
ZC3H8	XR_001738994.2 link	n.552G>A		non_coding_transcript_exon_variant	Exon 4 of 9
FBLN7	XR_007069507.1 link	n.10509-2546C>T		intron_variant	Intron 8 of 9
FBLN7	XR_007069508.1 link	n.10508+5690C>T		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZC3H8	ENST00000409573.7 link	c.491G>A	p.Gly164Asp	missense_variant	Exon 4 of 9	5	NM_032494.3	ENSP00000386488.1	Q8N5P1
ZC3H8	ENST00000466259.1 link	n.398G>A		non_coding_transcript_exon_variant	Exon 2 of 4	2
ZC3H8	ENST00000474234.5 link	n.671G>A		non_coding_transcript_exon_variant	Exon 5 of 7	5
ZC3H8	ENST00000464305.1 link	n.*11G>A		downstream_gene_variant		5

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

GnomAD3 exomes

AF:

0.00172

AC:

427

AN:

248586

Hom.:

AF XY:

0.00116

AC XY:

156

AN XY:

134870

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 SAS 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

Gnomad4 AFR exome

AF:

0.0237

Gnomad4 AMR exome

AF:

0.00155

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.00143

GnomAD4 genome

AF:

0.00736

AC:

1121

AN:

152296

Hom.:

Cov.:

AF XY:

0.00728

AC XY:

542

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0256

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000872

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Benign

0.022

T;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.70

.;T;T

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;.

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.32

N;N;.

REVEL

Benign

0.030

Sift

Benign

0.52

T;T;.

Sift4G

Benign

0.35

T;T;T

Polyphen

0.62

P;P;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over