11-110137018-T-C

Variant summary

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

The NM_033390.2(ZC3H12C):c.377T>C(p.Leu126Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000467 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: ZC3H12C NM_033390.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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=0.008063853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H12C	NM_033390.2	c.377T>C	p.Leu126Ser	missense_variant	2/6	ENST00000278590.8
ZC3H12C	NM_001411037.1	c.380T>C	p.Leu127Ser	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H12C	ENST00000278590.8	c.377T>C	p.Leu126Ser	missense_variant	2/6	2	NM_033390.2
ZC3H12C	ENST00000528673.5	c.380T>C	p.Leu127Ser	missense_variant	2/6	2
ZC3H12C	ENST00000453089.2	c.284T>C	p.Leu95Ser	missense_variant	1/5	2		P1
RDX	ENST00000645527.1	c.*251-5288A>G		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000646 AC: 160 AN: 247648 Hom.: 0 AF XY: 0.000603 AC XY: 81 AN XY: 134412

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00370

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.000680

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.000476 AC: 696 AN: 1461538 Hom.: 0 Cov.: 31 AF XY: 0.000443 AC XY: 322 AN XY: 727040

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00302

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00128

Gnomad4 NFE exome AF: 0.000447

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000691 Hom.: 0

Bravo AF: 0.000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000534 AC: 2

ESP6500EA AF: 0.000487 AC: 4

ExAC AF: 0.000579 AC: 70

EpiCase AF: 0.000382

EpiControl AF: 0.000890

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

Jan 27, 2022

The c.377T>C (p.L126S) alteration is located in exon 2 (coding exon 2) of the ZC3H12C gene. This alteration results from a T to C substitution at nucleotide position 377, causing the leucine (L) at amino acid position 126 to be replaced by a serine (S). 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	0.25
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.041	T;.;T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0081	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.8	M;.;.
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.17	T;T;D
Polyphen		0.31	B;.;.
Vest4		0.52
MVP		0.043
MPC		0.24
ClinPred		0.093	T
GERP RS		5.6
Varity_R		0.22
gMVP		0.49

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: rs182300452; hg19: chr11-110007743;