11-110136981-A-G

Variant summary

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

The NM_033390.2(ZC3H12C):c.340A>G(p.Thr114Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZC3H12C NM_033390.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

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=0.058332145).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H12C	NM_033390.2	c.340A>G	p.Thr114Ala	missense_variant	2/6	ENST00000278590.8
ZC3H12C	NM_001411037.1	c.343A>G	p.Thr115Ala	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H12C	ENST00000278590.8	c.340A>G	p.Thr114Ala	missense_variant	2/6	2	NM_033390.2
ZC3H12C	ENST00000528673.5	c.343A>G	p.Thr115Ala	missense_variant	2/6	2
ZC3H12C	ENST00000453089.2	c.247A>G	p.Thr83Ala	missense_variant	1/5	2		P1
RDX	ENST00000645527.1	c.*251-5251T>C		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

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

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247388 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134288

Gnomad AFR exome AF: 0.0000651

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726982

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.0000671 AC XY: 5 AN XY: 74478

Gnomad4 AFR AF: 0.000241

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000334 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.00000828 AC: 1

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

Dec 16, 2023

The c.340A>G (p.T114A) 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 340, causing the threonine (T) at amino acid position 114 to be replaced by an alanine (A). 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	0.066
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	10
Dann	Benign	0.92
DEOGEN2	Benign	0.012	T;.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.48	T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.058	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	0.67	N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.46	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0090	B;.;.
Vest4		0.20
MVP		0.043
MPC		0.032
ClinPred		0.049	T
GERP RS		5.4
Varity_R		0.067
gMVP		0.20

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

Other links and lift over

dbSNP: rs368637944; hg19: chr11-110007706;