ZNF711

protein-coding

zinc finger protein 711, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a zinc finger protein of unknown function. It bears similarity to a zinc finger protein which acts as a transcriptional activator. This gene lies in a region of the X chromosome which has been associated with cognitive disability. [provided by RefSeq, Jul 2008]

Previous symbols:

ZNF6
MRX65

MANE transcript

NM_001330574.2

Inheritance

ClinVar variants

P:17U:203B:32

Top phenotype

Intellectual developmental disorder, X-linked 97

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chrX:85,243,991-85,273,362

External References & Databases

Ensembl (ENSG00000147180)

Transcript & Mutation Effects

hg38 • Region Span ~29.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

intellectual developmental disorder, X-linked 97DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010430

Submitter: G2P

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*ZNF711* was first reported in relation to X-linked complex neurodevelopmental disorder (NDD) in 2009 by Tarpey et al. (PMID: 19377476) who reported a frameshift and nonsense variant transmitted within two large pedigrees with several affected males with intellectual disability and no other observable phenotypes. van der Werf et al. (2017, PMID: 27993705) reported two multigenerational families with X-linked complex NDD segregating with *ZNF711* variants (frameshift and missense). Four additional *ZNF711* variants were reported by Wang et al. (2022, PMID: 34992252); 3 nonsense variants and one *de novo* missense variant observed in families or individual probands affected by X-linked complex NDD. Segregation evidence from Tarpey et al. (2009), van der Werf et al. (2017), and Wang et al. (2022) resulted in 3 additional points. The maximum score for genetic evidence (12 points) was reached. Of note, missense variants in individual probands were of unclear pathogenicity and were not scored (PMIDs: 25649377, 28135719). An additional novel variant (c.127_129delGTT, p.V43del, GRCh37/hg19; ClinVar SCV:002030756.1) has been identified in a family affected by X-linked complex NDD enrolled in the Brain Gene Registry, but was not scored at this time. Experimental evidence implicates *ZNF711* in a regulatory network of syntenic, X-linked neurodevelopmental disorder-associated genes (*KDM5C, ARX, PHF8*) based on a series of studies demonstrating spatiotemporal expression patterns in developing human and mouse brains (PMID: 34356104), protein interactions (PMID: 31691806, PMID: 20346720), functional alteration in patient-derived cells (PMID: 34356104), and rescue experiments in cell culture models (PMID: 34356104 , PMID: 31691806) that are consistent with observed clinical phenotypes. In summary, there is definitive evidence supporting the relationship between *ZNF711* and X-linked complex neurodevelopmental disorder. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 3, 2020. It was reevaluated on September 22, 2022 (SOP Version 9). As a result of this reevaluation, the classification increased from Moderate to Definitive with the addition of new cases and experimental evidence.

intellectual developmental disorder, X-linked 97STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010430

Submitter: Ambry Genetics

intellectual developmental disorder, X-linked 97STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010430

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked 97STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010430

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 97XL

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: 19377476

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZNF711 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 103

Inborn genetic diseasesTotal: 56

Intellectual disability, X-linked 97Total: 41

not specifiedTotal: 27

ZNF711-related disorderTotal: 9

History of neurodevelopmental disorderTotal: 1

Inherited obesityTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001330574.2. 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			19 clinvar	15 clinvar	2 clinvar	36
missense		1 clinvar	169 clinvar	14 clinvar	1 clinvar	185
nonsense	2 clinvar	3 clinvar	4 clinvar			9
start loss						0
frameshift	5 clinvar	6 clinvar	2 clinvar			13
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	7	10	203	29	3	252

Highest pathogenic variant AF is 9.1150474e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 90 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001330574.2	RefSeq	NP_001317503.1	8	MANE Select
ENST00000674551.1	Ensembl	ENSP00000502839.1	8	MANE Select
NM_001375431.1	RefSeq	NP_001362360.1	8	Standard
NM_001375432.1	RefSeq	NP_001362361.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
Generic Transcription Pathway
RNA Polymerase II Transcription

Biological Process

regulation of transcription by RNA polymerase II
positive regulation of transcription, DNA-templated

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription factor activity
protein binding
chromatin DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373165
Coding exons: 7
Length: 29372
Individuals with no LoFs: 125346
Homozygous LoFs: 1
Heterozygous LoFs: 0
Defined: 125347
p: 0.00000399

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.40	165	278	0.594	0.0000194	5089
Missense (PolyPhen)		46	129.92	0.35406		2496
Synonymous	0.247	95	98.1	0.968	0.00000722	1361
Loss of Function	3.80	2	20.6	0.0970	0.00000174	386

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription regulator required for brain development. Probably acts as a transcription factor that binds to the promoter of target genes and recruits PHF8 histone demethylase, leading to activate expression of genes involved in neuron development, such as KDM5C. {ECO:0000269|PubMed:20346720}.;

Recessive Scores

pRec: 0.105

Intolerance Scores

RVIS EVS: -0.23
RVIS percentile EVS: 37.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.698

Gene Damage Prediction

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