11-110159488-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_033390.2(ZC3H12C):c.1146C>G(p.Asp382Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000751 in 1,598,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

ZC3H12C
NM_033390.2 missense, splice_region

Scores

Splicing: ADA: 0.9733

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.05

Variant links:

Genes affected

ZC3H12C (HGNC:29362): (zinc finger CCCH-type containing 12C) Predicted to enable endoribonuclease activity and mRNA binding activity. Predicted to be involved in RNA phosphodiester bond hydrolysis, endonucleolytic. Predicted to be active in cytoplasmic ribonucleoprotein granule and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZC3H12C links:

RDX (HGNC:9944): (radixin) Radixin is a cytoskeletal protein that may be important in linking actin to the plasma membrane. It is highly similar in sequence to both ezrin and moesin. The radixin gene has been localized by fluorescence in situ hybridization to 11q23. A truncated version representing a pseudogene (RDXP2) was assigned to Xp21.3. Another pseudogene that seemed to lack introns (RDXP1) was mapped to 11p by Southern and PCR analyses. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

RDX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H12C	NM_033390.2 linkuse as main transcript	c.1146C>G	p.Asp382Glu	missense_variant, splice_region_variant	4/6	ENST00000278590.8
ZC3H12C	NM_001411037.1 linkuse as main transcript	c.1149C>G	p.Asp383Glu	missense_variant, splice_region_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H12C	ENST00000278590.8 linkuse as main transcript	c.1146C>G	p.Asp382Glu	missense_variant, splice_region_variant	4/6	2	NM_033390.2		Q9C0D7-1
ZC3H12C	ENST00000528673.5 linkuse as main transcript	c.1149C>G	p.Asp383Glu	missense_variant, splice_region_variant	4/6	2			Q9C0D7-2
ZC3H12C	ENST00000453089.2 linkuse as main transcript	c.1053C>G	p.Asp351Glu	missense_variant, splice_region_variant	3/5	2		P1
RDX	ENST00000645527.1 linkuse as main transcript	c.*250+15479G>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152194

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000885

AC:

AN:

226080

Hom.:

AF XY:

0.00000821

AC XY:

AN XY:

121790

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:

0.0000199

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000691

AC:

AN:

1446200

Hom.:

Cov.:

AF XY:

0.00000418

AC XY:

AN XY:

717532

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:

0.00000725

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2021

The c.1146C>G (p.D382E) alteration is located in exon 4 (coding exon 4) of the ZC3H12C gene. This alteration results from a C to G substitution at nucleotide position 1146, causing the aspartic acid (D) at amino acid position 382 to be replaced by a glutamic acid (E). 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

0.98

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.46

T;.;T

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

0.025

MutationAssessor

Pathogenic

3.5

M;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Uncertain

0.45

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.96

MutPred

0.55

Loss of ubiquitination at K383 (P = 0.0982);.;.;

MVP

0.22

MPC

1.3

ClinPred

0.99

GERP RS

5.9

Varity_R

0.75

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.68

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