ZNF408

protein-coding

zinc finger protein 408, the group of PR/SET domain family|Zinc fingers C2H2-type

Gene summary

The protein encoded by this gene contains ten tandem zinc fingers and an N-terminal SET domain, so it is likely a DNA binding protein that interacts with other proteins. In adults, the encoded protein is expressed most highly in retina. Consequently, defects in this gene have been associated with familial exudative vitreoretinopathy (FEVR) and retinitis pigmentosa (RP). [provided by RefSeq, Dec 2016]

MANE transcript

NM_024741.3

Inheritance

AD, AR

ClinVar variants

P:23U:440B:209

Top phenotype

Exudative vitreoretinopathy 6; Retinitis pigmentosa 72

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr11:46,701,030-46,705,912

External References & Databases

Ensembl (ENSG00000175213)

Transcript & Mutation Effects

hg38 • Region Span ~4.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

exudative vitreoretinopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019516

Submitter: Orphanet

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

exudative vitreoretinopathy 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014652

Submitter: G2P

retinitis pigmentosa 72STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014653

Submitter: G2P

retinitis pigmentosa 72STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014653

Submitter: Labcorp Genetics (formerly Invitae)

exudative vitreoretinopathy 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014652

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosa 72STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014653

Submitter: PanelApp Australia

exudative vitreoretinopathy 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014652

Submitter: PanelApp Australia

retinitis pigmentosa 72MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014653

Submitter: Ambry Genetics

exudative vitreoretinopathy 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014652

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Exudative vitreoretinopathy 6; Retinitis pigmentosa 72AD/AR

Manifestation: Ophthalmologic

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: 6897033; 23716654; 25882705

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZNF408 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 616

Inborn genetic diseasesTotal: 101

not specifiedTotal: 95

Retinal dystrophyTotal: 35

ZNF408-related disorderTotal: 25

Exudative vitreoretinopathy 6Total: 12

Retinitis pigmentosa 72Total: 9

Exudative vitreoretinopathy 1Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024741.3. 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			5 clinvar	183 clinvar	3 clinvar	191
missense	1 clinvar	4 clinvar	399 clinvar	22 clinvar	1 clinvar	427
nonsense	1 clinvar	7 clinvar	11 clinvar			19
start loss			1 clinvar			1
frameshift	1 clinvar	6 clinvar	18 clinvar			25
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	6 clinvar			9
Total	5	18	440	205	4	672

Highest pathogenic variant AF is 0.000027281847

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024741.3	RefSeq	NP_079017.1	5	MANE Select
ENST00000311764.3	Ensembl	ENSP00000309606.2	5	MANE Select
NM_001184751.2	RefSeq	NP_001171680.1	5	Standard
ENST00000877975.1	Ensembl	ENSP00000548034.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
znf408	Danio rerio	Structure: ocular blood vessel Quality: morphology abnormal

Gene / Model

Organism

Observed Phenotype

znf408

Danio rerio

Structure: ocular blood vessel

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
identical protein binding
metal ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311764
Coding exons: 5
Length: 5095
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125748
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.712	403	445	0.905	0.0000270	4583
Missense (PolyPhen)		141	184.07	0.76601		1761
Synonymous	-0.249	190	186	1.02	0.0000104	1557
Loss of Function	2.29	14	26.8	0.522	0.00000157	272

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00032	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.00017	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in transcriptional regulation.;
Disease: DISEASE: Retinitis pigmentosa 72 (RP72) [MIM:616469]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:25882705}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0911

Intolerance Scores

LoFtool: 0.729
RVIS EVS: -1.02
RVIS percentile EVS: 8.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.947

Gene Damage Prediction

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