NM_032494.3:c.692A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032494.3(ZC3H8):c.692A>G(p.Gln231Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000137 in 1,601,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ZC3H8
NM_032494.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83

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 Uncertain_significance. Variant got 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
ZC3H8	NM_032494.3 link	c.692A>G	p.Gln231Arg	missense_variant	Exon 6 of 9	ENST00000409573.7	NP_115883.2	Q8N5P1
ZC3H8	XR_001738994.2 link	n.753A>G		non_coding_transcript_exon_variant	Exon 6 of 9
FBLN7	XR_007069507.1 link	n.10508+2416T>C		intron_variant	Intron 8 of 9
FBLN7	XR_007069508.1 link	n.10508+2416T>C		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZC3H8	ENST00000409573.7 link	c.692A>G	p.Gln231Arg	missense_variant	Exon 6 of 9	5	NM_032494.3	ENSP00000386488.1	Q8N5P1
ZC3H8	ENST00000466259.1 link	n.*34A>G		downstream_gene_variant		2
ZC3H8	ENST00000474234.5 link	n.*25A>G		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000432

AC:

AN:

231314

Hom.:

AF XY:

0.00

AC XY:

AN XY:

124990

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000961

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000145

AC:

AN:

1449268

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

719916

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000190

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.692A>G (p.Q231R) alteration is located in exon 6 (coding exon 6) of the ZC3H8 gene. This alteration results from a A to G substitution at nucleotide position 692, causing the glutamine (Q) at amino acid position 231 to be replaced by an arginine (R). 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

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Benign

-0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;T;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.86

.;D;T

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.92

L;L;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.8

N;N;.

REVEL

Benign

0.22

Sift

Benign

0.12

T;T;.

Sift4G

Benign

0.096

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.60

MutPred

0.52

Gain of MoRF binding (P = 0.1496);Gain of MoRF binding (P = 0.1496);Gain of MoRF binding (P = 0.1496);

MVP

0.32

MPC

0.68

ClinPred

0.79

GERP RS

5.2

Varity_R

0.21

gMVP

0.26

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

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