11-110136669-G-A

Position:

• chr11-110136669-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033390.2(ZC3H12C):​c.28G>A​(p.Gly10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000962 in 1,611,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: ZC3H12C NM_033390.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021260887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC3H12C	NM_033390.2	c.28G>A	p.Gly10Arg	missense_variant	2/6	ENST00000278590.8	NP_203748.1
ZC3H12C	NM_001411037.1	c.31G>A	p.Gly11Arg	missense_variant	2/6		NP_001397966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC3H12C	ENST00000278590.8	c.28G>A	p.Gly10Arg	missense_variant	2/6	2	NM_033390.2	ENSP00000278590.3
ZC3H12C	ENST00000528673.5	c.31G>A	p.Gly11Arg	missense_variant	2/6	2		ENSP00000431821.1
ZC3H12C	ENST00000453089.2	c.-66G>A		5_prime_UTR_variant	1/5	2		ENSP00000413094.2
RDX	ENST00000645527.1	n.*251-4939C>T		intron_variant				ENSP00000496121.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000122 AC: 30 AN: 245516 Hom.: 0 AF XY: 0.0000976 AC XY: 13 AN XY: 133180

Gnomad AFR exome AF: 0.000905

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.0000706 AC: 103 AN: 1459064 Hom.: 0 Cov.: 31 AF XY: 0.0000607 AC XY: 44 AN XY: 725448

Gnomad4 AFR exome AF: 0.000869

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000468

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74432

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000796 Hom.: 0

Bravo AF: 0.000408

ESP6500AA AF: 0.000796 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.28G>A (p.G10R) alteration is located in exon 2 (coding exon 2) of the ZC3H12C gene. This alteration results from a G to A substitution at nucleotide position 28, causing the glycine (G) at amino acid position 10 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	Benign	0.17
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.021	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.11	N;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.062
Sift	Benign	0.045	D;D
Sift4G	Benign	0.91	T;T
Polyphen		0.0020	B;.
Vest4		0.28
MutPred		0.50		Loss of sheet (P = 0.0181);.;
MVP		0.043
MPC		0.037
ClinPred		0.0063	T
GERP RS		2.4
Varity_R		0.094
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs201314969; hg19: chr11-110007394;