CD4

protein-coding

CD4 molecule, the group of V-set domain containing|CD molecules|C2-set domain containing

Gene summary

This gene encodes the CD4 membrane glycoprotein of T lymphocytes. The CD4 antigen acts as a coreceptor with the T-cell receptor on the T lymphocyte to recognize antigens displayed by an antigen presenting cell in the context of class II MHC molecules. The CD4 antigen is also a primary receptor for entry of the human immunodeficiency virus through interactions with the HIV Env gp120 subunit. This gene is expressed not only in T lymphocytes, but also in B cells, macrophages, granulocytes, as well as in various regions of the brain. The protein functions to initiate or augment the early phase of T-cell activation, and may function as an important mediator of indirect neuronal damage in infectious and immune-mediated diseases of the central nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been identified in this gene. [provided by RefSeq, May 2020]

MANE transcript

NM_000616.5

Inheritance

ClinVar variants

P:2U:26B:26

Top phenotype

Immunodeficiency 79

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr12:6,786,858-6,820,799

External References & Databases

Ensembl (ENSG00000010610)

Transcript & Mutation Effects

hg38 • Region Span ~33.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 79LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030981

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 79MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0030981

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Immunodeficiency 79AR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: The condition may involve early-onset and severe HPV, respiratory, and other infections, and awareness may allow early and agressive treatment of infections, as well as potential preventative measures

Refs: 6790623; 6209207; 6199335; 6199366; 6229573; 6208600; 1708753; 1961196; 7534484; 7541811; 7689618; 31781092; 33471124

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CD4 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 36

not providedTotal: 13

Immunodeficiency 79Total: 4

CD4-related disorderTotal: 4

Okt4 epitope deficiencyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000616.5. 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	15 clinvar	3 clinvar	20
missense			22 clinvar	5 clinvar	3 clinvar	30
nonsense						0
start loss	1 clinvar					1
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar		2 clinvar			3
Total	2	0	26	20	6	54

Highest pathogenic variant AF is 0.000016110183

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000616.5	RefSeq	NP_000607.1	9	MANE Select
ENST00000011653.9	Ensembl	ENSP00000011653.4	9	MANE Select
NM_001195014.3	RefSeq	NP_001181943.1	5	Standard
NM_001195015.3	RefSeq	NP_001181944.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antigen processing and presentation - Homo sapiens (human)
Primary immunodeficiency - Homo sapiens (human)
Cell adhesion molecules (CAMs) - Homo sapiens (human)
T cell receptor signaling pathway - Homo sapiens (human)
Th17 cell differentiation - Homo sapiens (human)

Biological Process

cytokine production
positive regulation of protein phosphorylation
adaptive immune response
induction by virus of host cell-cell fusion
immune response

Molecular Function

virus receptor activity
transmembrane signaling receptor activity
extracellular matrix structural constituent
protein binding
zinc ion binding

Cellular Component

early endosome
endoplasmic reticulum lumen
endoplasmic reticulum membrane
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000011653
Coding exons: 9
Length: 33951
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.06	206	253	0.813	0.0000136	2959
Missense (PolyPhen)		52	79.005	0.65819		1024
Synonymous	0.345	101	106	0.957	0.00000589	904
Loss of Function	2.59	9	22.1	0.406	9.94e-7	253

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000045	0.000044	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Integral membrane glycoprotein that plays an essential role in the immune response and serves multiple functions in responses against both external and internal offenses. In T-cells, functions primarily as a coreceptor for MHC class II molecule:peptide complex. The antigens presented by class II peptides are derived from extracellular proteins while class I peptides are derived from cytosolic proteins. Interacts simultaneously with the T-cell receptor (TCR) and the MHC class II presented by antigen presenting cells (APCs). In turn, recruits the Src kinase LCK to the vicinity of the TCR-CD3 complex. LCK then initiates different intracellular signaling pathways by phosphorylating various substrates ultimately leading to lymphokine production, motility, adhesion and activation of T- helper cells. In other cells such as macrophages or NK cells, plays a role in differentiation/activation, cytokine expression and cell migration in a TCR/LCK-independent pathway. Participates in the development of T-helper cells in the thymus and triggers the differentiation of monocytes into functional mature macrophages. {ECO:0000269|PubMed:16951326, ECO:0000269|PubMed:24942581, ECO:0000269|PubMed:2823150}.;

Recessive Scores

pRec: 0.984

Intolerance Scores

LoFtool: 0.837
RVIS EVS: 0.58
RVIS percentile EVS: 82.17

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.340

Gene Damage Prediction

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