ZNF335

protein-coding

zinc finger protein 335, the group of Zinc fingers C2H2-type

Gene summary

The protein encoded by this gene enhances transcriptional activation by ligand-bound nuclear hormone receptors. However, it does this not by direct interaction with the receptor, but by direct interaction with the nuclear hormone receptor transcriptional coactivator NRC. The encoded protein may function by altering local chromatin structure. [provided by RefSeq, Jul 2008]

MANE transcript

NM_022095.4

Inheritance

ClinVar variants

P:35U:363B:202

Top phenotype

Microcephaly 10, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr20:45,948,660-45,972,203

External References & Databases

Ensembl (ENSG00000198026)

Transcript & Mutation Effects

hg38 • Region Span ~23.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephalic primordial dwarfism due to ZNF335 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014043

Submitter: G2P

microcephalic primordial dwarfism due to ZNF335 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014043

Submitter: Labcorp Genetics (formerly Invitae)

microcephalic primordial dwarfism due to ZNF335 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014043

Submitter: PanelApp Australia

microcephalic primordial dwarfism due to ZNF335 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014043

Submitter: Ambry Genetics

microcephalic primordial dwarfism due to ZNF335 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014043

Submitter: Orphanet

Clinical Genomic Database (CGD)

Microcephaly 10, primary, autosomal recessiveAR

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: 23178126

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZNF335 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 491

Inborn genetic diseasesTotal: 229

Microcephalic primordial dwarfism due to ZNF335 deficiencyTotal: 66

not specifiedTotal: 60

ZNF335-related disorderTotal: 42

Autosomal recessive primary microcephalyTotal: 1

AutismTotal: 1

Aminoacylase 1 deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022095.4. 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			6 clinvar	154 clinvar	8 clinvar	168
missense	2 clinvar	8 clinvar	347 clinvar	37 clinvar	2 clinvar	396
nonsense	5 clinvar	3 clinvar	1 clinvar	1 clinvar		10
start loss						0
frameshift	7 clinvar	5 clinvar	3 clinvar			15
splice donor/acceptor (+/-2bp)		5 clinvar	6 clinvar			11
Total	14	21	363	192	10	600

Highest pathogenic variant AF is 0.00013074471

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022095.4	RefSeq	NP_071378.1	27	MANE Select
ENST00000322927.3	Ensembl	ENSP00000325326.2	27	MANE Select
ENST00000862673.1	Ensembl	ENSP00000532732.1	27	Standard
ENST00000862673.2	Ensembl	ENSP00000532732.1	27	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

in utero embryonic development
positive regulation of neuroblast proliferation
regulation of transcription by RNA polymerase II
brain development
regulation of gene expression

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II core promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
protein binding
transcription regulatory region DNA binding

Cellular Component

nucleus
nucleoplasm
histone methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000322927
Coding exons: 27
Length: 23542
Individuals with no LoFs: 125637
Homozygous LoFs: 2
Heterozygous LoFs: 109
Defined: 125748
p: 0.000441

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.550	795	840	0.947	0.0000529	8673
Missense (PolyPhen)		280	326.9	0.85652		3389
Synonymous	-0.632	360	345	1.04	0.0000228	2771
Loss of Function	4.83	23	65.0	0.354	0.00000335	710

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0.00043	0.00042	rare
European (Non-Finnish)	0.00055	0.00050	rare
South Asian	0.00030	0.00029	rare
Other	0.0011	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component or associated component of some histone methyltransferase complexes may regulate transcription through recruitment of those complexes on gene promoters. Enhances ligand- dependent transcriptional activation by nuclear hormone receptors. Plays an important role in neural progenitor cell proliferation and self-renewal through the regulation of specific genes involved brain development, including REST. Also controls the expression of genes involved in somatic development and regulates, for instance, lymphoblast proliferation. {ECO:0000269|PubMed:12215545, ECO:0000269|PubMed:18180299, ECO:0000269|PubMed:23178126}.;
Disease: DISEASE: Microcephaly 10, primary, autosomal recessive (MCPH10) [MIM:615095]: A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age- related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. MCPH10 is characterized by extremely small head size and death usually by 1 year of age. Neuropathologic examination shows severe loss of neurons as well as neuronal loss of polarity and abnormal dendritic maturation. {ECO:0000269|PubMed:23178126}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.625
RVIS EVS: -1.12
RVIS percentile EVS: 6.62

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.972

Gene Damage Prediction

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