KIAA1549

protein-coding

KIAA1549

Gene summary

The protein encoded by this gene belongs to the UPF0606 family. This gene has been found to be fused to the BRAF oncogene in many cases of pilocytic astrocytoma. The fusion results from 2Mb tandem duplications at 7q34. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

MANE transcript

NM_001164665.2

Inheritance

AD, AR

ClinVar variants

P:15U:903B:624

Top phenotype

Retinitis pigmentosa 86

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr7:138,831,381-138,981,389

External References & Databases

Ensembl (ENSG00000122778)

Transcript & Mutation Effects

hg38 • Region Span ~150.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

retinitis pigmentosa 86STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032834

Submitter: ClinGen

*KIAA1549* was first reported in relation to autosomal recessive retinitis pigmentosa in 2018 (de Bruijn et al., PMID: 30120214). Five homozygous variants (One missense, one nonsense, three frameshift) that have been reported in five probands in four publications (PMIDs: 30120214, 31213501, 36819107, 23105016) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be biallelic loss-of-function. This gene-disease association is also supported by qPCR experiments showing that *KIAA1549* is highly and specifically expressed in the human retina. This same group goes on to use immunofluorescence experiments of mouse retinal sections to show that *KIAA1549* is localized to the connecting cilium of photoreceptor cells, and at the outer plexiform layer of the mouse retina (PMID: 30120214). Supporting these results, another mouse model also shows *KIAA1549* localization to the outer plexiform layer, as well as in the outer and inner segments of photoreceptor cells (PMID: 34027671). In summary, *KIAA1549* is Strongly associated with autosomal recessive retinitis pigmentosa. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Retina GCEP on February 6, 2025 (SOP Version 9).

retinitis pigmentosa 86MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032834

Submitter: Ambry Genetics

retinitis pigmentosa 86STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032834

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: G2P

Clinical Genomic Database (CGD)

Retinitis pigmentosa 86AR

Manifestation: Ophthalmologic

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

Refs: 30120214

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KIAA1549 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 1444

Inborn genetic diseasesTotal: 355

not specifiedTotal: 285

Retinal dystrophyTotal: 99

KIAA1549-related disorderTotal: 54

Retinitis pigmentosa 86Total: 22

Optic atrophyTotal: 3

Retinitis pigmentosaTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001164665.2. 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			14 clinvar	517 clinvar	4 clinvar	535
missense		1 clinvar	871 clinvar	96 clinvar	7 clinvar	975
nonsense		2 clinvar	5 clinvar			7
start loss			1 clinvar			1
frameshift	3 clinvar	7 clinvar	7 clinvar			17
splice donor/acceptor (+/-2bp)		2 clinvar	5 clinvar			7
Total	3	12	903	613	11	1542

Highest pathogenic variant AF is 0.00008769967

Loading ClinVar variants...

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_001164665.2	RefSeq	NP_001158137.1	20	MANE Select
ENST00000422774.2	Ensembl	ENSP00000416040.2	20	MANE Select
NM_020910.3	RefSeq	NP_065961.2	20	Standard
ENST00000440172.5	Ensembl	ENSP00000406661.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Disease
Signaling by BRAF and RAF fusions
Oncogenic MAPK signaling
Diseases of signal transduction

Biological Process

regulation of transcription by RNA polymerase II

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000422774
Coding exons: 20
Length: 149939
Individuals with no LoFs: 124645
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 124674
p: 0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0923	1121	1.11e+3	1.01	0.0000698	12426
Missense (PolyPhen)		388	445.27	0.87137		4725
Synonymous	-1.23	525	490	1.07	0.0000360	4249
Loss of Function	6.15	12	65.9	0.182	0.00000351	779

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Note=A chromosomal aberration involving KIAA1549 is found in pilocytic astrocytoma. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation. {ECO:0000269|PubMed:18974108}.;

Recessive Scores

pRec: 0.104

Intolerance Scores

LoFtool: 0.494
RVIS EVS: 1.66
RVIS percentile EVS: 96.24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0789

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High