HERC4

protein-coding

HECT and RLD domain containing E3 ubiquitin protein ligase 4, the group of HECT and RLD domain containing E3 ubiquitin protein ligases

Gene summary

HERC4 belongs to the HERC family of ubiquitin ligases, all of which contain a HECT domain and at least 1 RCC1 (MIM 179710)-like domain (RLD). The 350-amino acid HECT domain is predicted to catalyze the formation of a thioester with ubiquitin before transferring it to a substrate, and the RLD is predicted to act as a guanine nucleotide exchange factor for small G proteins (Hochrainer et al., 2005 [PubMed 15676274]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_015601.4

Inheritance

—

ClinVar variants

U:81B:4

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr10:67,921,899-68,075,301

External References & Databases

Ensembl (ENSG00000148634)

Transcript & Mutation Effects

hg38 • Region Span ~153.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HERC4 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 70

not providedTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015601.4. 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			1 clinvar	2 clinvar		3
missense			71 clinvar	2 clinvar		73
nonsense						0
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	0	0	81	4	0	85

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 110 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015601.4	RefSeq	NP_056416.2	23	MANE Select
ENST00000373700.9	Ensembl	ENSP00000362804.4	23	MANE Select
NM_001278185.2	RefSeq	NP_001265114.1	22	Standard
NM_001278186.2	RefSeq	NP_001265115.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation
Class I MHC mediated antigen processing & presentation

Biological Process

spermatogenesis
protein ubiquitination
cell differentiation

Molecular Function

ubiquitin-protein transferase activity

Cellular Component

fibrillar center
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395198
Coding exons: 24
Length: 153441
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125744
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.31	256	537	0.477	0.0000256	6948
Missense (PolyPhen)		42	175.34	0.23953		2259
Synonymous	1.59	162	190	0.854	0.00000937	1975
Loss of Function	5.88	7	53.4	0.131	0.00000235	715

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00015	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable E3 ubiquitin-protein ligase involved in either protein trafficking or in the distribution of cellular structures. Required for spermatozoon maturation and fertility, and for the removal of the cytoplasmic droplet of the spermatozoon. E3 ubiquitin-protein ligases accept ubiquitin from an E2 ubiquitin- conjugating enzyme in the form of a thioester and then directly transfer it to targeted substrates. {ECO:0000250|UniProtKB:Q6PAV2}.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.409
RVIS EVS: -1.09
RVIS percentile EVS: 7.11

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.679

Gene Damage Prediction

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