ZC3H14

protein-coding

zinc finger CCCH-type containing 14, the group of Zinc fingers CCCH-type

Gene summary

The protein encoded by this gene is a poly(A)-binding protein that can affect gene expression and poly(A) tail length. The encoded protein may influence mRNA stability, nuclear export, and translation. [provided by RefSeq, May 2016]

MANE transcript

NM_024824.5

Inheritance

AR, AD

ClinVar variants

P:1U:94B:34

Top phenotype

Intellectual developmental disorder, autosomal recessive 56

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr14:88,562,970-88,627,596

External References & Databases

Ensembl (ENSG00000100722)

Transcript & Mutation Effects

hg38 • Region Span ~64.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 56LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014930

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 56MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014930

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 56LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014930

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disabilityLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: ClinGen

*ZC3H14* encodes a zinc finger CCCH domain-containing protein that belongs to a family of polyadenosine RNA binding proteins that influence gene expression. *ZC3H14* was first reported in relation to autosomal recessive intellectual disability in 2011 (Pak et al., PMID: 21734151). Three siblings with mild-moderate intellectual disability in a consanguineous family were reported with a homozygous nonsense *ZC3H14* variant (PMID: 21734151). A second consanguineous family with 3 siblings with severe intellectual disability harboring a homozygous intronic *ZC3H14* variant was reported in the same publication (PMID: 21734151); however, this variant is found at a high frequency in gnomAD v4.1.1 and was not scored. This gene-disease relationship is also supported by experiments in *Zc3h14* knockout mice and Drosophila null for the *Nab2* ortholog (PMIDs: 21734151, 28666327). In summary, there is limited evidence to support the relationship between *ZC3H14* and autosomal recessive intellectual disability. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts this gene-disease relationship. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 16, 2022. It was reevaluated on August 24, 2026. As a result of this reevaluation, no additional patients were identified and the classification did not change. The scoring was updated to be consistent with SOP Version 12.

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 56AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21734151

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZC3H14 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 109

not providedTotal: 36

ZC3H14-related disorderTotal: 10

Intellectual disability, autosomal recessive 56Total: 10

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024824.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	24 clinvar	1 clinvar	28
missense			85 clinvar	8 clinvar	1 clinvar	94
nonsense	1 clinvar		1 clinvar			2
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	0	94	32	2	129

Highest pathogenic variant AF is 0.0000013681089

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 121 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024824.5	RefSeq	NP_079100.2	17	MANE Select
ENST00000251038.10	Ensembl	ENSP00000251038.5	17	MANE Select
NM_001160103.2	RefSeq	NP_001153575.1	17	Standard
NM_001160104.2	RefSeq	NP_001153576.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of mRNA stability
negative regulation of mRNA polyadenylation

Molecular Function

RNA binding
protein binding
poly(A) binding
metal ion binding

Cellular Component

nucleus
nucleolus
cytoplasm
nuclear speck
dendrite cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000251038
Coding exons: 17
Length: 50601
Individuals with no LoFs: 125617
Homozygous LoFs: 0
Heterozygous LoFs: 131
Defined: 125748
p: 0.000521

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.45	317	399	0.795	0.0000206	4870
Missense (PolyPhen)		105	179.01	0.58656		2204
Synonymous	-1.80	166	139	1.19	0.00000761	1371
Loss of Function	4.88	8	42.2	0.189	0.00000245	477

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0053	0.0053	notable
Latino/Admixed American	0.00049	0.00049	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in poly(A) tail length control in neuronal cells. Binds the polyadenosine RNA oligonucleotides. {ECO:0000269|PubMed:17630287, ECO:0000269|PubMed:24671764}.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.0287
RVIS EVS: -0.64
RVIS percentile EVS: 16.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.788

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium