chr11-110093424-G-T

Variant names:

• chr11-110093424-G-T
• rs768813122
• NM_033390.2:c.13G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033390.2(ZC3H12C):​c.13G>T​(p.Gly5Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,053,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. G5R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: ZC3H12C NM_033390.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.693
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17845136).

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.13G>T	p.Gly5Cys	missense	Exon 1 of 6	NP_203748.1	Q9C0D7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H12C	ENST00000278590.8	TSL:2 MANE Select	c.13G>T	p.Gly5Cys	missense	Exon 1 of 6	ENSP00000278590.3	Q9C0D7-1
	RDX	ENST00000645527.1		n.*757+30635C>A		intron	N/A	ENSP00000496121.1	A0A2R8Y7M3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1053952 Hom.: 0 Cov.: 33 AF XY: 0.00000201 AC XY: 1 AN XY: 498406

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21492

American (AMR) AF: 0.00 AC: 0 AN: 7502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12514

East Asian (EAS) AF: 0.00 AC: 0 AN: 22884

South Asian (SAS) AF: 0.00 AC: 0 AN: 19426

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3036

European-Non Finnish (NFE) AF: 0.00000222 AC: 2 AN: 899436

Other (OTH) AF: 0.00 AC: 0 AN: 41032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.37	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.69
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.059
Sift	Uncertain	0.017	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.67	P
Vest4		0.22
MutPred		0.18		Loss of disorder (P = 0.0448)
MVP		0.068
MPC		0.038
ClinPred		0.26	T
GERP RS		1.9
PromoterAI		-0.035	Neutral
Varity_R		0.13
gMVP		0.29
Mutation Taster		=96/4	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768813122; hg19: chr11-109964150;