ZNF462

protein-coding

zinc finger protein 462, the group of Zinc fingers C2H2-type

Gene summary

The protein encoded by this gene belongs to C2H2-type zinc finger family of proteins. It contains multiple C2H2-type zinc fingers and may be involved in transcriptional regulation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

MANE transcript

NM_021224.6

Inheritance

ClinVar variants

P:95U:500B:216

Top phenotype

Weiss-Kruszka syndrome

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr9:106,863,166-107,013,634

External References & Databases

Ensembl (ENSG00000148143)

Transcript & Mutation Effects

hg38 • Region Span ~150.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Weiss-Kruszka syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032836

Submitter: Ambry Genetics

Weiss-Kruszka syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032836

Submitter: G2P

Weiss-Kruszka syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032836

Submitter: Illumina

ZNF462 was first reported in relation to autosomal dominant Weiss-Kruszka syndrome in 2017 (28513610: Weiss et al. 2017). At least seven unique loss-of-function variants have been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least seven probands from two publications (28513610: Weiss et al. 2017; 31361404: Kruszka et al. 2019). Majority of the variants were de novo and in one family, a variant in this gene segregated with disease in four additional family members. In one four-generation family. The mechanism for disease is heterozygous, loss of function variants. This gene-disease association is supported by expression studies that demonstrate a higher expression in fetal brain and liver, and varying expression in the brain in different developmental stages of mice. Animal models suggest that ZNF462 plays a crucial role in during vertebrate embryonic development and Zfp462+/− mice recapitulate the clinical presentation in humans (11347906: Nagase et al. 2017; 19111535: Laurent et al. 2009; 27621227: Wang et al. 2017). In summary, ZNF462 is definitively associated with autosomal dominant ZNF462-related spectrum disorder.

Weiss-Kruszka syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032836

Submitter: Labcorp Genetics (formerly Invitae)

Weiss-Kruszka syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032836

Submitter: ClinGen

The ZNF462 gene was first reported in relation to autosomal dominant Weiss-Kruszka syndrome in 2017 (Weiss et al., 2017 PMID 28513610). At least seven unique loss-of-function variants have been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least seven probands from two publications (Weiss et al., 2017 PMID 28513610; Kruszka et al., 2019 PMID 31361404). The majority of reported variants are de novo, with one family showing segregation of a variant in this gene in four additional affected family members. The mechanism for disease is mono-allelic loss of function. This gene-disease relationship is supported by expression studies that demonstrate higher expression of ZNF462 in fetal brain and liver, and varying expression in the brain in different developmental stages in mice. Animal models suggest that ZNF462 plays a crucial role in vertebrate embryonic development with Zfp462+/− mice presenting with developmental abnormalities and anxiety-like behaviors (Nagase et al., 2017 PMID 11347906; Laurent et al., 2009 PMID 19111535; Wang et al., 2017 PMID 27621227). In summary, ZNF462 is definitively associated with autosomal dominant Weiss-Kruszka syndrome. This classification was approved by the ClinGen Syndromic Disorders GCEP on 7.17.2020 (SOP Version 7).

Weiss-Kruszka syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032836

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Weiss-Kruszka syndromeAD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 28513610; 31361404

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZNF462 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 358

Inborn genetic diseasesTotal: 290

Weiss-Kruszka syndromeTotal: 121

ZNF462-related disorderTotal: 97

not specifiedTotal: 79

Craniosynostosis syndromeTotal: 3

Intellectual disability, autosomal dominantTotal: 3

Familial cancer of breastTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021224.6. 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			2 clinvar	116 clinvar	5 clinvar	123
missense		2 clinvar	489 clinvar	92 clinvar	3 clinvar	586
nonsense	22 clinvar	12 clinvar	3 clinvar			37
start loss						0
frameshift	33 clinvar	23 clinvar	2 clinvar			58
splice donor/acceptor (+/-2bp)	3 clinvar		4 clinvar			7
Total	58	37	500	208	8	811

Highest pathogenic variant AF is 0.00037252673

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021224.6	RefSeq	NP_067047.4	12	MANE Select
ENST00000277225.10	Ensembl	ENSP00000277225.5	12	MANE Select
NM_001347997.2	RefSeq	NP_001334926.1	12	Standard
ENST00000374686.6	Ensembl	ENSP00000363818.2	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mesodermal Commitment Pathway

Biological Process

chromatin organization
regulation of gene expression
negative regulation of DNA binding
positive regulation of transcription by RNA polymerase II

Molecular Function

RNA polymerase II core promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
metal ion binding

Cellular Component

nucleus
histone methyltransferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000277225
Coding exons: 12
Length: 150538
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125748
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.35	1058	1.41e+3	0.749	0.0000831	16669
Missense (PolyPhen)		340	626.49	0.5427		7441
Synonymous	-1.40	601	559	1.08	0.0000354	4759
Loss of Function	8.56	3	91.2	0.0329	0.00000554	1120

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in transcriptional regulation.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.413
RVIS EVS: -2.81
RVIS percentile EVS: 0.64

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.369

Gene Damage Prediction

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