PHF5A

protein-coding

PHD finger protein 5A, the group of PHD finger proteins|SF3b complex

Gene summary

This gene encodes a subunit of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence-independent manner and may anchor the U2 snRNP to the pre-mRNA. The protein encoded by this gene contains a PHD-finger-like domain that is flanked by highly basic N- and C-termini. This protein belongs to the PHD-finger superfamily and may act as a chromatin-associated protein. This gene has several pseudogenes on different chromosomes. [provided by RefSeq, Jul 2008]

MANE transcript

NM_032758.4

Inheritance

ClinVar variants

P:4U:9

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr22:41,459,717-41,468,692

External References & Databases

Ensembl (ENSG00000100410)

Transcript & Mutation Effects

hg38 • Region Span ~9.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHF5A variants in ClinVar

3 Conditions Cataloged

not providedTotal: 9

PHF5A-related disorderTotal: 3

Inborn genetic diseasesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032758.4. 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						0
missense	1 clinvar		4 clinvar			5
nonsense	1 clinvar		1 clinvar			2
start loss		1 clinvar				1
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)	1 clinvar		2 clinvar			3
Total	3	1	9	0	0	13

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032758.4	RefSeq	NP_116147.1	4	MANE Select
ENST00000216252.4	Ensembl	ENSP00000216252.3	4	MANE Select
ENST00000899733.1	Ensembl	ENSP00000569792.1	5	Standard
ENST00000899733.2	Ensembl	ENSP00000569792.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
phf5a	Danio rerio	Structure: trunk Quality: curved dorsal abnormal

Gene / Model

Organism

Observed Phenotype

phf5a

Danio rerio

Structure: trunk

Quality: curved dorsal

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Spliceosome - Homo sapiens (human)
mRNA Processing
Metabolism of RNA
mRNA Splicing - Major Pathway
mRNA Splicing

Biological Process

mRNA splicing, via spliceosome
positive regulation of transcription, DNA-templated

Molecular Function

DNA binding
DNA-binding transcription factor activity
RNA binding
metal ion binding

Cellular Component

nucleoplasm
U2 snRNP
U12-type spliceosomal complex
nuclear matrix
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000216252
Coding exons: 4
Length: 9009
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	2.65	5	65.4	0.0765	0.00000355	718
Missense (PolyPhen)		3	22.269	0.13472		261
Synonymous	-0.547	25	21.8	1.15	0.00000108	196
Loss of Function	2.38	0	6.58	0.00	3.73e-7	81

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: Involved with the PAF1 complex (PAF1C) in transcriptional elongation by RNA polymerase II, and in regulation of development and maintenance of embryonic stem cell (ESC) pluripotency. Required for maintenance of ESCs self-renewal and cellular reprogramming of stem cells. Maintains pluripotency by recruiting and stabilizing PAF1C on pluripotency genes loci, and by regulating the expression of the pluripotency genes. Regulates the deposition of elongation-associated histone modifications, including dimethylated histone H3 'Lys-79' (H3K79me2) and trimethylated histone H3 'Lys-36' (H3K36me3), on PAF1C targets, self-renewal and pluripotency genes. Regulates RNA polymerase II promoter-proximal pause release of the PAF1C targets and self- renewal genes, and the levels of elongating ('Ser-2' phosphorylated) RNA polymerase II in their gene bodies. Regulates muscle specification in adult stem cells by stabilizing PAF1C in chromatin to promote myogenic differentiation (By similarity). Involved in pre-mRNA splicing as a component of the splicing factor SF3B complex (PubMed:27720643, PubMed:28541300). SF3B complex is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence (BPS) in pre-mRNA. Sequence independent binding of SF3A/SF3B complex upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA (PubMed:12234937). Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha (By similarity). {ECO:0000250|UniProtKB:P83870, ECO:0000250|UniProtKB:P83871, ECO:0000269|PubMed:12234937, ECO:0000269|PubMed:27720643, ECO:0000269|PubMed:28541300}.;

Recessive Scores

pRec: 0.149

Intolerance Scores

RVIS EVS: 0.15
RVIS percentile EVS: 63.81

Essentials

Essential (CRISPR): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.539