HIVEP2

protein-coding

HIVEP zinc finger 2, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a member of a family of closely related, large, zinc finger-containing transcription factors. The encoded protein regulates transcription by binding to regulatory regions of various cellular and viral genes that maybe involved in growth, development and metastasis. The protein contains the ZAS domain comprised of two widely separated regions of zinc finger motifs, a stretch of highly acidic amino acids and a serine/threonine-rich sequence. [provided by RefSeq, Nov 2012]

MANE transcript

NM_006734.4

Inheritance

ClinVar variants

P:87U:678B:727

Top phenotype

Mental retardation, autosomal dominant 43

gnomAD constraint

pLI —, LoF o/e 0.03

Max pathogenic AF

—

Genomic locus

chr6:142,751,469-142,956,698

External References & Databases

Ensembl (ENSG00000010818)

Transcript & Mutation Effects

hg38 • Region Span ~205.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015802

Submitter: Orphanet

intellectual developmental disorder, autosomal dominant 43STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014858

Submitter: Illumina

The HIVEP2 gene was first reported in relation to autosomal dominant HIVEP2-related intellectual disability in 2012 (23020937: Rauch et al. 2012). At least six unique variants have been reported in three papers, all of which are de novo, loss of function variants (four null, and two frameshift variants) (23020937: Rauch et al. 2012; 26153216: Srivastava et al. 2016; 27003583: Steinfeld et al. 2016). Evidence supporting this gene-disease relationship includes case-level data and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence experimental evidence (12 pts.) has been reached. This gene-disease relationship is supported by a homozygous knockout mouse model which exhibited anxiety, increased stress, cognitive impairment, hyperactivity and other brain anomalies; and studies showing interaction with, and expression in the developing brain and co-localisation with, SEF2 (now TCF4), a gene associated with intellectual disability. In summary, there is strong evidence to support the relationship between HIVEP2 and HIVEP2-related intellectual disability (autosomal dominant). Additional reports in humans are needed to reach a definitive classification

intellectual developmental disorder, autosomal dominant 43STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014858

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal dominant 43DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014858

Submitter: G2P

intellectual developmental disorder, autosomal dominant 43STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014858

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mental retardation, autosomal dominant 43AD

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: 23020937; 26153216; 27003583

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HIVEP2 variants in ClinVar

18 Conditions Cataloged

not providedTotal: 1149

Inborn genetic diseasesTotal: 330

Intellectual disability, autosomal dominant 43Total: 180

not specifiedTotal: 134

HIVEP2-related disorderTotal: 104

Intellectual disabilityTotal: 8

See casesTotal: 8

Angelman syndrome-likeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006734.4. 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			8 clinvar	261 clinvar	109 clinvar	378
missense	1 clinvar	4 clinvar	663 clinvar	328 clinvar	28 clinvar	1024
nonsense	27 clinvar	6 clinvar	4 clinvar			37
start loss						0
frameshift	27 clinvar	20 clinvar	2 clinvar	1 clinvar		50
splice donor/acceptor (+/-2bp)		2 clinvar	1 clinvar			3
Total	55	32	678	590	137	1492

Highest pathogenic variant AF is 0.0000013681145

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006734.4	RefSeq	NP_006725.3	6	MANE Select
ENST00000367603.8	Ensembl	ENSP00000356575.2	6	MANE Select
NM_001438449.1	RefSeq	NP_001425378.1	6	Standard
NM_001438450.1	RefSeq	NP_001425379.1	6	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

nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367603
Coding exons: 6
Length: 193735
Individuals with no LoFs: 124789
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 124796
p: 0.0000280

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.83	1129	1.32e+3	0.858	0.0000739	16010
Missense (PolyPhen)		317	516.63	0.61359		6391
Synonymous	-0.942	547	520	1.05	0.0000319	4889
Loss of Function	8.02	2	78.8	0.0254	0.00000432	1068

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein specifically binds to the DNA sequence 5'- GGGACTTTCC-3' which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV1. In addition, related sequences are found in the enhancer elements of a number of cellular promoters, including those of the class I MHC, interleukin-2 receptor, somatostatin receptor II, and interferon- beta genes. It may act in T-cell activation.;
Disease: DISEASE: Mental retardation, autosomal dominant 43 (MRD43) [MIM:616977]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD43 patients manifest developmental delay, intellectual disability, hypotonia, and dysmorphic features. {ECO:0000269|PubMed:23020937, ECO:0000269|PubMed:26153216}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.156

Intolerance Scores

LoFtool: 0.0160
RVIS EVS: -2.2
RVIS percentile EVS: 1.37

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.852

Gene Damage Prediction

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