chr11-110137018-T-C

Variant names:

• chr11-110137018-T-C
• rs182300452
• NM_033390.2:c.377T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. 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
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008063853).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033390.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H12C	NM_033390.2	MANE Select	c.377T>C	p.Leu126Ser	missense	Exon 2 of 6	NP_203748.1	Q9C0D7-1
	ZC3H12C	NM_001411037.1		c.380T>C	p.Leu127Ser	missense	Exon 2 of 6	NP_001397966.1	Q9C0D7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H12C	ENST00000278590.8	TSL:2 MANE Select	c.377T>C	p.Leu126Ser	missense	Exon 2 of 6	ENSP00000278590.3	Q9C0D7-1
	ZC3H12C	ENST00000528673.5	TSL:2	c.380T>C	p.Leu127Ser	missense	Exon 2 of 6	ENSP00000431821.1	Q9C0D7-2
	ZC3H12C	ENST00000453089.2	TSL:2	c.284T>C	p.Leu95Ser	missense	Exon 1 of 5	ENSP00000413094.2	E9PP00

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

GnomAD2 exomes AF: 0.000646 AC: 160 AN: 247648 AF XY: 0.000603

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00128 AC: 68 AN: 53304

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000447 AC: 497 AN: 1111846

Other (OTH) AF: 0.000513 AC: 31 AN: 60372

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

African (AFR) AF: 0.00 AC: 0 AN: 41574

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000651 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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
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
Mutation Taster		=70/30	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: rs182300452; hg19: chr11-110007743;