AFF4

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

Basic information

Region (hg38): 5:132875394-132963634

Links

ENSG00000072364 ∙ NCBI:27125 ∙ OMIM:604417 ∙ HGNC:17869 ∙ Uniprot:Q9UHB7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (Strong), mode of inheritance: AD
• cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (Supportive), mode of inheritance: AD
• cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cognitive impairment, coarse facies, Heart defects, Obesity, Pulmonary involvement, Short stature, and skeletal dysplasia (CHOPS syndrome)	AD	Cardiovascular	Individuals have been described with congenital heart anomalies, and awareness may enable early diagnosis and management	Cardiovascular; Craniofacial; Genitourinary; Musculoskeletal; Neurologic; Pulmonary	25730767

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the AFF4 gene.

• Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome (285 variants)
• not provided (72 variants)
• Inborn genetic diseases (36 variants)
• AFF4-related condition (23 variants)
• not specified (11 variants)
• Primary dilated cardiomyopathy (1 variants)
• Autism spectrum disorder (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the AFF4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	53	11	66
missense		4	171	20	3	198
nonsense			1			1
start loss						0
frameshift			3			3
inframe indel			6			6
splice donor/acceptor (+/-2bp)			4	1		5
splice region			4	9	2	15
non coding			3	33	32	68
Total	0	4	190	107	46

Variants in AFF4

This is a list of pathogenic ClinVar variants found in the AFF4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
5-132881049-T-C		AFF4-related disorder	Likely benign (Oct 25, 2022)
5-132881071-C-T		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Likely benign (Jun 05, 2023)
5-132881076-C-T		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Uncertain significance (Nov 24, 2022)
5-132881085-G-A			Uncertain significance (Jul 11, 2019)
5-132881101-C-T		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Likely benign (Dec 31, 2019)
5-132881119-T-A		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome • AFF4-related disorder	Likely benign (Sep 08, 2023)
5-132881126-G-A		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Uncertain significance (Nov 10, 2023)
5-132881137-T-C		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Likely benign (Jun 29, 2022)
5-132881140-A-G		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Likely benign (Aug 23, 2022)
5-132881203-A-G		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Likely benign (Sep 20, 2023)
5-132881203-A-T		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Likely benign (Jan 19, 2023)
5-132881375-C-A			Benign (May 23, 2021)
5-132883095-C-A			Benign (May 08, 2021)
5-132883258-A-G			Benign (May 23, 2021)
5-132883321-T-C		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Likely benign (Oct 03, 2023)
5-132883333-T-C		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Uncertain significance (May 10, 2022)
5-132883346-G-C		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Uncertain significance (Aug 08, 2023)
5-132883351-T-C		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Uncertain significance (Jun 01, 2021)
5-132883361-G-C			Uncertain significance (Aug 01, 2022)
5-132883383-G-A		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome • AFF4-related disorder	Benign/Likely benign (Aug 04, 2023)
5-132883384-G-A		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Uncertain significance (Jan 24, 2024)
5-132883385-T-C		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome • AFF4-related disorder	Benign/Likely benign (Jan 19, 2024)
5-132883392-G-C		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome • AFF4-related disorder	Likely benign (Jan 01, 2024)
5-132883397-A-T			Uncertain significance (Jul 24, 2020)
5-132883415-C-T		Cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome	Uncertain significance (Aug 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
AFF4	protein_coding	protein_coding	ENST00000265343	20	88256

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	1.80e-7	125738	0	7	125745	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.47	450	624	0.721	0.0000336	7662
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000148	0.000148
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.0000545	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000176	0.0000176
Middle Eastern	0.0000545	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

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.
• Pathway: 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 (Consensus)

Recessive Scores

• pRec: 0.113

Intolerance Scores

• loftool: 0.260
• rvis_EVS: -0.55
• rvis_percentile_EVS: 19.8

Haploinsufficiency Scores

• pHI: 0.706
• hipred: Y
• hipred_score: 0.853
• ghis: 0.622

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.982

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Aff4
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; embryo phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); reproductive system phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: regulation of transcription, DNA-templated;transcription by RNA polymerase II;transcription elongation from RNA polymerase II promoter;spermatid development
• Cellular component: fibrillar center;nucleus;nucleoplasm;transcription elongation factor complex;ELL-EAF complex;transcriptionally active chromatin
• Molecular function: double-stranded DNA binding;DNA-binding transcription factor activity;protein binding