11-110136897-A-G

Variant names:

• chr11-110136897-A-G
• rs1189117329
• NM_033390.2:c.256A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033390.2(ZC3H12C):​c.256A>G​(p.Ser86Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000656 in 152,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: ZC3H12C NM_033390.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.48
• Publications: 1 publications found

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]

RDX Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 24

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1544284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H12C	NM_033390.2	c.256A>G	p.Ser86Gly	missense_variant	Exon 2 of 6	ENST00000278590.8	NP_203748.1
ZC3H12C	NM_001411037.1	c.259A>G	p.Ser87Gly	missense_variant	Exon 2 of 6		NP_001397966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC3H12C	ENST00000278590.8	c.256A>G	p.Ser86Gly	missense_variant	Exon 2 of 6	2	NM_033390.2	ENSP00000278590.3
ZC3H12C	ENST00000528673.5	c.259A>G	p.Ser87Gly	missense_variant	Exon 2 of 6	2		ENSP00000431821.1
ZC3H12C	ENST00000453089.2	c.163A>G	p.Ser55Gly	missense_variant	Exon 1 of 5	2		ENSP00000413094.2
RDX	ENST00000645527.1	n.*251-5167T>C		intron_variant	Intron 15 of 18			ENSP00000496121.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74498

African (AFR) AF: 0.0000240 AC: 1 AN: 41588

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.256A>G (p.S86G) alteration is located in exon 2 (coding exon 2) of the ZC3H12C gene. This alteration results from a A to G substitution at nucleotide position 256, causing the serine (S) at amino acid position 86 to be replaced by a glycine (G). 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	0.087
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;T
Eigen	Benign	0.020
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L;.;.
PhyloP100		4.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.070	N;N;N
REVEL	Benign	0.081
Sift	Benign	0.058	T;T;T
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.31	B;.;.
Vest4		0.47
MutPred		0.13		Loss of phosphorylation at S86 (P = 0.0057);.;.;
MVP		0.043
MPC		0.083
ClinPred		0.52	D
GERP RS		5.4
Varity_R		0.070
gMVP		0.14
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1189117329; hg19: chr11-110007622;