11-110137086-T-C

Variant names:

• chr11-110137086-T-C
• rs1325841742
• NM_033390.2:c.445T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033390.2(ZC3H12C):​c.445T>C​(p.Ser149Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S149T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZC3H12C NM_033390.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.031612962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H12C	NM_033390.2	c.445T>C	p.Ser149Pro	missense_variant	Exon 2 of 6	ENST00000278590.8	NP_203748.1
ZC3H12C	NM_001411037.1	c.448T>C	p.Ser150Pro	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.445T>C	p.Ser149Pro	missense_variant	Exon 2 of 6	2	NM_033390.2	ENSP00000278590.3
ZC3H12C	ENST00000528673.5	c.448T>C	p.Ser150Pro	missense_variant	Exon 2 of 6	2		ENSP00000431821.1
ZC3H12C	ENST00000453089.2	c.352T>C	p.Ser118Pro	missense_variant	Exon 1 of 5	2		ENSP00000413094.2
RDX	ENST00000645527.1	n.*251-5356A>G		intron_variant	Intron 15 of 18			ENSP00000496121.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248378 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000890

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.7
DANN	Benign	0.95
DEOGEN2	Benign	0.012	T;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.57	T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L;.;.
PhyloP100		-1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.16	N;N;N
REVEL	Benign	0.016
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.081
MutPred		0.13		Loss of phosphorylation at S149 (P = 0.0346);.;.;
MVP		0.043
MPC		0.038
ClinPred		0.032	T
GERP RS		-1.2
Varity_R		0.077
gMVP		0.14
Mutation Taster		=94/6	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: rs1325841742; hg19: chr11-110007811;