AFF3

protein-coding

ALF transcription elongation factor 3, the group of AF4/FMR2 family|Super elongation complex

Gene summary

This gene encodes a tissue-restricted nuclear transcriptional activator that is preferentially expressed in lymphoid tissue. Isolation of this protein initially defined a highly conserved LAF4/MLLT2 gene family of nuclear transcription factors that may function in lymphoid development and oncogenesis. In some ALL patients, this gene has been found fused to the gene for MLL. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

LAF4

MANE transcript

NM_001386135.1

Inheritance

ClinVar variants

P:16U:237B:74

Top phenotype

KINSSHIP syndrome

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr2:99,545,419-100,192,428

External References & Databases

Ensembl (ENSG00000144218)

Transcript & Mutation Effects

hg38 • Region Span ~647.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

KINSSHIP syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0851095

Submitter: G2P

KINSSHIP syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0851095

Submitter: PanelApp Australia

KINSSHIP syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0851095

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disabilityMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: G2P

Clinical Genomic Database (CGD)

KINSSHIP syndromeAD

Manifestation: Craniofacial; Dermatologic; Musculoskeletal; Neurologic; Pulmonary; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial to allow interventions such as preserving eggs in women with premature ovarian insufficiency

Refs: 31388108; 33961779

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AFF3 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 167

not providedTotal: 101

AFF3-related disorderTotal: 57

not specifiedTotal: 55

KINSSHIP syndromeTotal: 24

See casesTotal: 3

AFF3-related neurodevelopmental disordersTotal: 1

AFF3-associated disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001386135.1. 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	42 clinvar	5 clinvar	52
missense	6 clinvar	6 clinvar	218 clinvar	25 clinvar	2 clinvar	257
nonsense		1 clinvar	4 clinvar			5
start loss						0
frameshift	1 clinvar	2 clinvar	6 clinvar			9
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	7	9	237	67	7	327

Highest pathogenic variant AF is 0.0000093096805

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001386135.1	RefSeq	NP_001373064.1	22	MANE Select
ENST00000672756.2	Ensembl	ENSP00000500419.1	22	MANE Select
NM_001025108.2	RefSeq	NP_001020279.1	23	Standard
NM_002285.3	RefSeq	NP_002276.2	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription, DNA-templated
response to tumor necrosis factor
embryonic hindlimb morphogenesis

Molecular Function

double-stranded DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
cytosol
transcription elongation factor complex
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356421
Coding exons: 23
Length: 596879
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125748
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.71	607	738	0.823	0.0000441	8221
Missense (PolyPhen)		136	210.11	0.64728		2511
Synonymous	0.228	312	317	0.984	0.0000226	2437
Loss of Function	6.30	7	59.4	0.118	0.00000311	693

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Putative transcription activator that may function in lymphoid development and oncogenesis. Binds, in vitro, to double- stranded DNA.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.441
RVIS EVS: -1.46
RVIS percentile EVS: 3.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.892

Gene Damage Prediction

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