HHLA2

protein-coding

HERV-H LTR-associating 2, the group of V-set domain containing|C1-set domain containing|B7 family

Gene summary

This gene encodes a protein ligand found on the surface of monocytes. The encoded protein is thought to regulate cell-mediated immunity by binding to a receptor on T lymphocytes and inhibiting the proliferation of these cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

MANE transcript

NM_001282556.2

Inheritance

—

ClinVar variants

U:57B:5

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.62

Max pathogenic AF

—

Genomic locus

chr3:108,296,529-108,378,285

External References & Databases

Ensembl (ENSG00000114455)

Transcript & Mutation Effects

hg38 • Region Span ~81.8 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 HHLA2 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 57

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001282556.2. 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			2 clinvar			2
missense			53 clinvar	5 clinvar		58
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	0	57	5	0	62

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 78 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001282556.2	RefSeq	NP_001269485.1	8	MANE Select
ENST00000467761.6	Ensembl	ENSP00000419207.1	8	MANE Select
NM_001282557.2	RefSeq	NP_001269486.1	8	Standard
NM_001282558.2	RefSeq	NP_001269487.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

positive regulation of cytokine production
T cell costimulation
positive regulation of activated T cell proliferation
regulation of immune response
T cell receptor signaling pathway

Molecular Function

molecular_function
signaling receptor binding
protein binding

Cellular Component

cellular_component
external side of plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357759
Coding exons: 8
Length: 81757
Individuals with no LoFs: 124564
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 124585
p: 0.0000843

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.573	194	218	0.891	0.0000111	2720
Missense (PolyPhen)		25	31.888	0.784		394
Synonymous	1.77	62	82.4	0.752	0.00000479	757
Loss of Function	1.55	12	19.3	0.621	9.06e-7	249

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00073	0.00072	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.00018	0.00016	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Through interaction with TMIGD2, costimulates T-cells in the context of TCR-mediated activation. Enhances T-cell proliferation and cytokine production via an AKT-dependent signaling cascade. {ECO:0000269|PubMed:23784006}.;

Recessive Scores

pRec: 0.0708

Intolerance Scores

LoFtool: 0.844
RVIS EVS: 1.82
RVIS percentile EVS: 96.99

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.283

Gene Damage Prediction

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