11-110137110-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033390.2(ZC3H12C):c.469G>A(p.Asp157Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00032 in 1,613,840 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: ZC3H12C NM_033390.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.97

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007570654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZC3H12C	NM_033390.2	c.469G>A	p.Asp157Asn	missense_variant	2/6	ENST00000278590.8
ZC3H12C	NM_001411037.1	c.472G>A	p.Asp158Asn	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZC3H12C	ENST00000278590.8	c.469G>A	p.Asp157Asn	missense_variant	2/6	2	NM_033390.2
ZC3H12C	ENST00000528673.5	c.472G>A	p.Asp158Asn	missense_variant	2/6	2
ZC3H12C	ENST00000453089.2	c.376G>A	p.Asp126Asn	missense_variant	1/5	2		P1
RDX	ENST00000645527.1	c.*251-5380C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000608 AC: 151 AN: 248302 Hom.: 1 AF XY: 0.000609 AC XY: 82 AN XY: 134668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000755

Gnomad ASJ exome AF: 0.00528

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000688

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000328 AC: 479 AN: 1461532 Hom.: 2 Cov.: 31 AF XY: 0.000347 AC XY: 252 AN XY: 727008

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000510

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74468

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000654 Hom.: 0

Bravo AF: 0.000374

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000563 AC: 68

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000416

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

Sep 27, 2021

The c.469G>A (p.D157N) 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 469, causing the aspartic acid (D) at amino acid position 157 to be replaced by an asparagine (N). 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	0.084
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.016	T;.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0076	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.72	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.095	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.96	P;.;.
Vest4		0.20
MVP		0.068
MPC		0.033
ClinPred		0.10	T
GERP RS		5.6
Varity_R		0.051
gMVP		0.26

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: rs200420973; hg19: chr11-110007835; COSMIC: COSV53714072;