EIF4A3

protein-coding

eukaryotic translation initiation factor 4A3, the group of SSU processome|DEAD-box helicases|Spliceosomal Bact complex|Spliceosomal P complex|Exon junction complex

Gene summary

This gene encodes a member of the DEAD box protein family. DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure, such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene is a nuclear matrix protein. Its amino acid sequence is highly similar to the amino acid sequences of the translation initiation factors eIF4AI and eIF4AII, two other members of the DEAD box protein family. [provided by RefSeq, Jul 2008]

Previous symbols:

DDX48

MANE transcript

NM_014740.4

Inheritance

ClinVar variants

P:1U:31B:14

Top phenotype

Richieri-Costa-Pereira Syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:80,134,369-80,147,151

External References & Databases

Ensembl (ENSG00000141543)

Transcript & Mutation Effects

hg38 • Region Span ~12.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Richieri Costa-Pereira syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009998

Submitter: Labcorp Genetics (formerly Invitae)

Richieri Costa-Pereira syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009998

Submitter: Ambry Genetics

Richieri Costa-Pereira syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009998

Submitter: PanelApp Australia

Richieri Costa-Pereira syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009998

Submitter: G2P

Richieri Costa-Pereira syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009998

Submitter: Orphanet

Clinical Genomic Database (CGD)

Richieri-Costa-Pereira SyndromeAR

Manifestation: Craniofacial; Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The genetic cause involves a noncoding expansion

Refs: 24360810

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EIF4A3 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 24

not providedTotal: 14

not specifiedTotal: 8

EIF4A3-related disorderTotal: 4

Richieri Costa-Pereira syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014740.4. 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			1 clinvar	11 clinvar	3 clinvar	15
missense	1 clinvar		28 clinvar			29
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	0	31	11	3	46

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014740.4	RefSeq	NP_055555.1	12	MANE Select
ENST00000649764.2	Ensembl	ENSP00000497641.1	12	MANE Select
NM_001411099.1	RefSeq	NP_001398028.1	11	Standard
ENST00000576547.2	Ensembl	ENSP00000460439.2	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mRNA surveillance pathway - Homo sapiens (human)
RNA transport - Homo sapiens (human)
Spliceosome - Homo sapiens (human)
Gene expression (Transcription)
Cytokine Signaling in Immune system

Biological Process

nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
mRNA splicing, via spliceosome
rRNA processing
RNA export from nucleus
mRNA export from nucleus

Molecular Function

RNA binding
mRNA binding
ATP-dependent RNA helicase activity
protein binding
ATP binding

Cellular Component

nucleoplasm
cytoplasm
cytosol
membrane
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000269349
Coding exons: 12
Length: 11970
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.02	74	255	0.291	0.0000146	2698
Missense (PolyPhen)		20	113.12	0.17681		1178
Synonymous	-0.814	106	95.9	1.11	0.00000578	782
Loss of Function	4.64	0	25.0	0.00	0.00000131	270

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	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: ATP-dependent RNA helicase (PubMed:16170325). Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:22961380, PubMed:28502770, PubMed:28076346). Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Its RNA-dependent ATPase and RNA-helicase activities are induced by CASC3, but abolished in presence of the MAGOH-RBM8A heterodimer, thereby trapping the ATP- bound EJC core onto spliced mRNA in a stable conformation. The inhibition of ATPase activity by the MAGOH-RBM8A heterodimer increases the RNA-binding affinity of the EJC. Involved in translational enhancement of spliced mRNAs after formation of the 80S ribosome complex. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Shows higher affinity for single-stranded RNA in an ATP-bound core EJC complex than after the ATP is hydrolyzed. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly (PubMed:22203037). Involved in craniofacial development (PubMed:24360810). {ECO:0000269|PubMed:11991638, ECO:0000269|PubMed:15034551, ECO:0000269|PubMed:16170325, ECO:0000269|PubMed:16209946, ECO:0000269|PubMed:17375189, ECO:0000269|PubMed:19409878, ECO:0000269|PubMed:22203037, ECO:0000269|PubMed:22961380, ECO:0000269|PubMed:24360810, ECO:0000269|PubMed:28076346, ECO:0000269|PubMed:28502770}.;

Recessive Scores

pRec: 0.203

Intolerance Scores

RVIS EVS: -0.63
RVIS percentile EVS: 17.03

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.994

Gene Damage Prediction

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