ZNF292

protein-coding

zinc finger protein 292, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a growth hormone-dependent, zinc finger transcription factor that functions as a tumor suppressor. Naturally occurring mutations in this gene are associated with gastric cancer, colorectal cancer, and chronic lymphocytic leukemia. [provided by RefSeq, May 2017]

MANE transcript

NM_015021.3

Inheritance

ClinVar variants

P:126U:539B:264

Top phenotype

Intellectual developmental disorder, autosomal dominant 64

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr6:87,151,803-87,265,943

External References & Databases

Ensembl (ENSG00000188994)

Transcript & Mutation Effects

hg38 • Region Span ~114.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal dominant 64STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030934

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*ZNF292* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2012 (PMIDs: 22495311, 23033978). Over 20 unique *de novo* truncating variants have been reported in over 30 probands (PMIDs: 22495311, 23033978, 28135719, 31723249). Individuals with *ZNF292* truncating variants present with neurodevelopmental phenotypes (including intellectual disability/developmental delay, speech delays and autism spectrum disorder) and minor dysmorphic features. Although most reported variants are *de novo*, one *ZNF292* truncating variant was inherited from an affected mother with mild ID (PMID: 31723249). In addition, three affected siblings inherited a *ZNF292* truncating variant from a reportedly unaffected father, suggesting reduced penetrance (PMID: 31723249). *ZNF292* is highly intolerant to truncating variants (pLI = 1 in gnomAD). Currently, there are no experimental data delineating the disease mechanism. Most reported variants are located in the last exon, which encodes for a DNA binding domain; these variants are predicted to escape nonsense-mediated decay, leading to the expression of a truncated protein with potential dominant-negative or gain-of function effects (PMID: 31723249). However, the possibility of loss of function cannot be ruled out, and functional studies will be necessary to determine the molecular mechanism of pathogenicity. In summary, there is definitive evidence supporting the relationship between *ZNF292* and autosomal dominant complex neurodevelopmental disorders. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 6, 2020 (SOP Version 7).

intellectual developmental disorder, autosomal dominant 64STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030934

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal dominant 64STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030934

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 64AD

Manifestation: Craniofacial; Musculoskeletal; 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: 31723249

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZNF292 variants in ClinVar

19 Conditions Cataloged

not providedTotal: 388

Inborn genetic diseasesTotal: 381

Intellectual developmental disorder, autosomal dominant 64Total: 136

ZNF292-related disorderTotal: 96

not specifiedTotal: 75

Neurodevelopmental disorderTotal: 35

Intellectual disabilityTotal: 9

Complex neurodevelopmental disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015021.3. 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			4 clinvar	90 clinvar	6 clinvar	100
missense		6 clinvar	510 clinvar	158 clinvar	9 clinvar	683
nonsense	12 clinvar	30 clinvar	8 clinvar			50
start loss			1 clinvar			1
frameshift	26 clinvar	52 clinvar	12 clinvar	1 clinvar		91
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	38	88	539	249	15	929

Highest pathogenic variant AF is 0.00002194338

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015021.3	RefSeq	NP_055836.1	8	MANE Select
ENST00000369577.8	Ensembl	ENSP00000358590.3	8	MANE Select
NM_001351444.2	RefSeq	NP_001338373.1	5	Standard
ENST00000339907.8	Ensembl	ENSP00000342847.4	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of transcription by RNA polymerase II

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369577
Coding exons: 8
Length: 111364
Individuals with no LoFs: 124585
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 124612
p: 0.000108

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.41	1203	1.35e+3	0.892	0.0000667	17948
Missense (PolyPhen)		202	433.73	0.46572		5788
Synonymous	-2.14	553	493	1.12	0.0000247	5096
Loss of Function	8.30	7	93.8	0.0747	0.00000516	1306

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00019	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.00037	0.00037	rare
European (Non-Finnish)	0.00012	0.000097	rare
South Asian	0.000099	0.000098	rare
Other	0.00017	0.00017	rare

dbNSFP Gene Annotations

Source: dbNSFP

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

Recessive Scores

pRec: 0.151

Intolerance Scores

LoFtool: 0.282
RVIS EVS: -1.15
RVIS percentile EVS: 6.29

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.776

Gene Damage Prediction

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