AFF4

protein-coding

ALF transcription elongation factor 4, the group of Super elongation complex|AF4/FMR2 family

Gene summary

The protein encoded by this gene belongs to the AF4 family of transcription factors involved in leukemia. It is a component of the positive transcription elongation factor b (P-TEFb) complex. A chromosomal translocation involving this gene and MLL gene on chromosome 11 is found in infant acute lymphoblastic leukemia with ins(5;11)(q31;q31q23). [provided by RefSeq, Oct 2011]

MANE transcript

NM_014423.4

Inheritance

ClinVar variants

P:8U:483B:227

Top phenotype

Cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia (CHOPS syndrome)

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr5:132,875,395-132,963,634

External References & Databases

Ensembl (ENSG00000072364)

Transcript & Mutation Effects

hg38 • Region Span ~88.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014609

Submitter: Orphanet

cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014609

Submitter: Labcorp Genetics (formerly Invitae)

cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014609

Submitter: G2P

cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014609

Submitter: PanelApp Australia

cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014609

Submitter: Illumina

Clinical Genomic Database (CGD)

Cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia (CHOPS syndrome)AD

Manifestation: Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Pulmonary

Intervention: Cardiovascular

Rationale: Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management

Refs: 25730767

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AFF4 variants in ClinVar

10 Conditions Cataloged

Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndromeTotal: 494

AFF4-related disorderTotal: 391

Inborn genetic diseasesTotal: 138

not providedTotal: 125

not specifiedTotal: 49

Primary dilated cardiomyopathyTotal: 1

Congenital ocular colobomaTotal: 1

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014423.4. 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			5 clinvar	169 clinvar	7 clinvar	181
missense	1 clinvar	7 clinvar	455 clinvar	48 clinvar	2 clinvar	513
nonsense			4 clinvar			4
start loss						0
frameshift			9 clinvar			9
splice donor/acceptor (+/-2bp)			10 clinvar	1 clinvar		11
Total	1	7	483	218	9	718

Highest pathogenic variant AF is 6.842089e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014423.4	RefSeq	NP_055238.1	20	MANE Select
ENST00000265343.10	Ensembl	ENSP00000265343.5	20	MANE Select
ENST00000378595.7	Ensembl	ENSP00000367858.3	12	Standard
ENST00000378595.8	Ensembl	ENSP00000367858.3	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
RNA Polymerase II Pre-transcription Events
Formation of RNA Pol II elongation complex
RNA Polymerase II Transcription
RNA Polymerase II Transcription Elongation

Biological Process

regulation of transcription, DNA-templated
transcription by RNA polymerase II
transcription elongation from RNA polymerase II promoter
spermatid development

Molecular Function

double-stranded DNA binding
DNA-binding transcription factor activity
protein binding

Cellular Component

fibrillar center
nucleus
nucleoplasm
transcription elongation factor complex
ELL-EAF complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265343
Coding exons: 20
Length: 88256
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125745
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.47	450	624	0.721	0.0000336	7662
Missense (PolyPhen)		214	339.07	0.63113		4234
Synonymous	1.24	203	227	0.895	0.0000120	2211
Loss of Function	6.58	3	56.3	0.0533	0.00000309	710

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. In the SEC complex, AFF4 acts as a central scaffold that recruits other factors through direct interactions with ELL proteins (ELL, ELL2 or ELL3) and the P-TEFb complex. In case of infection by HIV-1 virus, the SEC complex is recruited by the viral Tat protein to stimulate viral gene expression. {ECO:0000269|PubMed:20159561, ECO:0000269|PubMed:20471948, ECO:0000269|PubMed:23251033}.;
Disease: DISEASE: Note=A chromosomal aberration involving AFF4 is found in acute lymphoblastic leukemia (ALL). Insertion ins(5;11)(q31;q13q23) that forms a KMT2A/MLL1-AFF4 fusion protein.; DISEASE: CHOPS syndrome (CHOPS) [MIM:616368]: A syndrome characterized by cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia. {ECO:0000269|PubMed:25730767}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.260
RVIS EVS: -0.55
RVIS percentile EVS: 19.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.982

Gene Damage Prediction

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