KIFBP

protein-coding

kinesin family binding protein, the group of Tetratricopeptide repeat domain containing

Gene summary

This gene encodes a kinesin family member 1 binding protein that is characterized by two tetratrico peptide repeats. The encoded protein localizes to the mitochondria and may be involved in regulating transport of the mitochondria. Mutations in this gene are associated with Goldberg-Shprintzen megacolon syndrome. [provided by RefSeq, Mar 2010]

Previous symbols:

KIAA1279
KIF1BP

MANE transcript

NM_015634.4

Inheritance

ClinVar variants

P:17U:137B:43

Top phenotype

Goldberg-Shprintzen megacolon syndrome

gnomAD constraint

pLI —, LoF o/e 0.27

Max pathogenic AF

—

Genomic locus

chr10:68,988,803-69,043,544

External References & Databases

Ensembl (ENSG00000198954)

Transcript & Mutation Effects

hg38 • Region Span ~54.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Goldberg-Shprintzen syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012280

Submitter: G2P

Goldberg-Shprintzen syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012280

Submitter: Labcorp Genetics (formerly Invitae)

Goldberg-Shprintzen syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012280

Submitter: ClinGen

KIFBP (alternative titles KBP, KIAA1279) was first reported in relation to autosomal recessive Goldberg-Shprintzen syndrome (GOSHS; OMIM# 609460) in 2005 (Brooks et al., PMID: 15883926). GOSHS is characterized by intellectual disability and microcephaly, frequently seen with Hirschsprung disease and/or gyral abnormalities of the brain. Nine homozygous loss of function variants (nonsense, frameshift, intragenic deletion) that have been reported in ten probands in six publications (PMIDs: 15883926, 23427148, 24072599, 28277559, 32939943, 34421502) are included in this curation. All of these ten probands were homozygous variant carriers, eight of which were from families known to be consanguineous, many of which had more than one affected homozygote. 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 loss of function. While missense variants have been reported in cases with atypical presentations (PMID: 32939943), there is insufficient evidence to support a pathogenic role for missense variants in this disease at this time. This gene-disease relationship is also supported by a zebrafish kbp mutant model organism that displays disruption in axonal structure (PMID: 23427148) and a human cell culture model that shows abnormal neurite outgrowth (PMID: 18192286), mirroring the central and enteric neuronal developmental defects seen in GOSHS. In summary, there is definitive evidence supporting the relationship between KIFBP and autosomal recessive GOSHS. 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 Brain Malformations GCEP on the meeting date July 25, 2023 (SOP Version 9).

Goldberg-Shprintzen syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012280

Submitter: Orphanet

Goldberg-Shprintzen syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012280

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Goldberg-Shprintzen megacolon syndromeAR

Manifestation: Gastrointestinal; Neurologic

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: 7338549; 10874640; 15883926

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KIFBP variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 116

not providedTotal: 108

Goldberg-Shprintzen syndromeTotal: 55

KIFBP-related disorderTotal: 5

EpilepsyTotal: 2

KIF1BP-related disordersTotal: 1

Peripheral neuropathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015634.4. 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			4 clinvar	34 clinvar	1 clinvar	39
missense			130 clinvar	8 clinvar		138
nonsense	5 clinvar	2 clinvar	1 clinvar			8
start loss						0
frameshift	4 clinvar	5 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	9	8	137	42	1	197

Highest pathogenic variant AF is 0.0001883769

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015634.4	RefSeq	NP_056449.1	7	MANE Select
ENST00000361983.7	Ensembl	ENSP00000354848.4	7	MANE Select
ENST00000626493.2	Ensembl	ENSP00000486692.1	6	Standard
ENST00000626493.3	Ensembl	ENSP00000486692.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kif1bp	Danio rerio	Structure: neuron Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

kif1bp

Danio rerio

Structure: neuron

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrial transport
nervous system development
cell differentiation

Molecular Function

protein binding
kinesin binding

Cellular Component

mitochondrion
cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000361983
Coding exons: 7
Length: 28252
Individuals with no LoFs: 125674
Homozygous LoFs: 0
Heterozygous LoFs: 73
Defined: 125747
p: 0.000290

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.45	255	329	0.775	0.0000159	4074
Missense (PolyPhen)		68	91.641	0.74202		1174
Synonymous	1.57	104	127	0.822	0.00000597	1184
Loss of Function	3.42	7	25.7	0.272	0.00000116	346

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.0028	0.0028	notable
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00030	0.00030	rare
South Asian	0.00010	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for organization of axonal microtubules, and axonal outgrowth and maintenance during peripheral and central nervous system development. {ECO:0000269|PubMed:16225668, ECO:0000269|PubMed:20621975, ECO:0000269|PubMed:23427148}.;

Recessive Scores

pRec: 0.153

Intolerance Scores

RVIS EVS: -0.33
RVIS percentile EVS: 30.7

Essentials

Essential (gene trap): N