ZNF81

protein-coding

zinc finger protein 81, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a protein that likely functions as a transcription factor. The protein contains an N-terminal KRAB domain and several C2H2-type zinc finger motifs. Mutations in this gene cause an X-linked form of intellectual disability (MRX45). Microduplication of a region of chromosome X including this gene has also been associated with other forms of intellectual disability. [provided by RefSeq, Jul 2017]

Previous symbols:

MRX45

MANE transcript

NM_007137.5

Inheritance

ClinVar variants

U:65B:26

Top phenotype

Mental retardation, X-linked 45

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chrX:47,836,902-48,002,561

External References & Databases

Ensembl (ENSG00000197779)

Transcript & Mutation Effects

hg38 • Region Span ~165.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked intellectual disabilityNO_KNOWN

Inheritance Pattern: XL

Disease ID:MONDO:0100284

Submitter: ClinGen

The relationship between ZNF81 and X-linked intellectual disability was first reported by Kleefstra et al. in 2004 (PMID: 15121780). They reported a female with severe intellectual disability carrying a de novo X;9 translocation disrupting ZNF81 on chromosome X and EHMT1 on chromosome 9. Variants in EHMT1 cause an autosomal dominant intellectual disability syndrome (Kleefstra syndrome), so this translocation cannot be used as evidence. Sequencing of ZNF81 in families with X-linked intellectual disability identified a missense variant in affected males within a multigenerational pedigree. This variant is present in gnomAD (v2.1.1) 18 times (including 6 males) and was not scored as evidence. No other genetic variants have been reported. In summary, there is no valid genetic evidence supporting the association between ZNF81 and non-syndromic X-linked intellectual disability, so this gene-disease relationship is disputed. Of note, this gene-disease pair was originally evaluated by the Intellectual Disability and Autism Gene Curation Expert Panel on 06/28/2018, and reevaluated on 01/26/2021. As a result of this reevaluation, the original classification of “disputed” did not change. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 01/26/2021 (SOP Version 8).

X-linked intellectual disabilityNO_KNOWN

Inheritance Pattern: XL

Disease ID:MONDO:0100284

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked 45LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0010344

Submitter: Labcorp Genetics (formerly Invitae)

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

Clinical Genomic Database (CGD)

Mental retardation, X-linked 45XL

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

Comments: The evidence of variants as being related to disease causation has been questioned due to subsequent population-based studies

Refs: 10398246; 15121780; 23871722

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZNF81 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 68

not providedTotal: 18

ZNF81-related disorderTotal: 11

History of neurodevelopmental disorderTotal: 3

Intellectual disability, X-linked 45Total: 1

Non-syndromic X-linked intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007137.5. 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			2 clinvar	10 clinvar	3 clinvar	15
missense			61 clinvar	9 clinvar	4 clinvar	74
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	65	19	7	91

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 26 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_007137.5	RefSeq	NP_009068.2	4	MANE Select
ENST00000338637.13	Ensembl	ENSP00000341151.7	4	MANE Select
NM_001378152.1	RefSeq	NP_001365081.1	4	Standard
NM_001378153.1	RefSeq	NP_001365082.1	4	Standard

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
metal ion binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376954
Coding exons: 4
Length: 165660
Individuals with no LoFs: 125391
Homozygous LoFs: 2
Heterozygous LoFs: 4
Defined: 125397
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.42	168	229	0.735	0.0000155	4428
Missense (PolyPhen)		47	90.623	0.51863		1816
Synonymous	0.673	73	80.7	0.905	0.00000553	1155
Loss of Function	2.92	3	15.4	0.195	0.00000105	347

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000074	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00013	0.000092	rare
European (Non-Finnish)	0.000037	0.000018	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.;
Disease: DISEASE: Note=A chromosomal aberration involving ZNF81 is found in a severe mental retardation patient. Translocation t(X;9)(p11.23;q34.3). {ECO:0000269|PubMed:15121780}.;

Recessive Scores

pRec: 0.158

Intolerance Scores

LoFtool: 0.346
RVIS EVS: 1.57
RVIS percentile EVS: 95.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.888

Gene Damage Prediction

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