MACF1

microtubule actin crosslinking factor 1, the group of EF-hand domain containing|Plakins

Basic information

Region (hg38): 1:39081315-39487177

Previous symbols: [ "KIAA0754" ]

Links

ENSG00000127603 ∙ NCBI:23499 ∙ OMIM:608271 ∙ HGNC:13664 ∙ Uniprot:O94854, Q9UPN3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lissencephaly 9 with complex brainstem malformation (Moderate), mode of inheritance: AD
• lissencephaly 9 with complex brainstem malformation (Strong), mode of inheritance: AD
• lissencephaly 9 with complex brainstem malformation (Supportive), mode of inheritance: AD
• lissencephaly 9 with complex brainstem malformation (Strong), mode of inheritance: AD
• lissencephaly spectrum disorder with complex brainstem malformation (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Lissencephaly 9 with complex brainstem malformation	AD	General	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	Neurologic	24507697; 30471716

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the MACF1 gene.

• not provided (640 variants)
• Inborn genetic diseases (210 variants)
• Lissencephaly 9 with complex brainstem malformation (97 variants)
• MACF1-related condition (20 variants)
• Spectraplakinopathy type I (6 variants)
• not specified (5 variants)
• See cases (5 variants)
• Intellectual disability (2 variants)
• Abnormal corpus callosum morphology (2 variants)
• lissencephaly with brainstem hypoplasia (1 variants)
• Lissencephaly with decussation defect (1 variants)
• Lissencephaly (1 variants)
• Seizure (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the MACF1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	91	39	131
missense	2	4	323	145	37	511
nonsense	1		18			19
start loss						0
frameshift		1	7			8
inframe indel			3	1		4
splice donor/acceptor (+/-2bp)			11			11
splice region			10	10	12	32
non coding			11	31	103	145
Total	3	5	374	268	179

Variants in MACF1

This is a list of pathogenic ClinVar variants found in the MACF1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-39084210-G-A		MACF1-related disorder	Likely benign (May 25, 2021)
1-39084245-CAGTGAGCGGTCATGTCGG-C			Uncertain significance (Dec 25, 2021)
1-39084245-C-CAGTGAGCGGTCATGTCGG		MACF1-related disorder • Inborn genetic diseases	Likely benign (Aug 11, 2023)
1-39084245-C-CAGTGAGCGGTCATGTCGGAGTGAGCGGTCATGTCGG			Benign (Dec 03, 2023)
1-39084253-G-A		Lissencephaly 9 with complex brainstem malformation • Inborn genetic diseases	Conflicting classifications of pathogenicity (Apr 11, 2023)
1-39084257-ATGTCGGAGTGAGCGGTCT-A			Uncertain significance (Jan 02, 2024)
1-39084257-A-ATGTCGGAGTGAGCGGTCT			Uncertain significance (Nov 28, 2023)
1-39084270-C-T			Uncertain significance (Jul 16, 2023)
1-39084272-GTCTTGTCGGAGTGAGCGA-G			Uncertain significance (May 01, 2023)
1-39084295-AC-A			Uncertain significance (Jul 14, 2022)
1-39084297-A-G			Uncertain significance (Sep 02, 2021)
1-39084302-C-T			Likely benign (Jan 18, 2024)
1-39084307-G-A		Inborn genetic diseases • Lissencephaly 9 with complex brainstem malformation	Uncertain significance (Jun 10, 2023)
1-39084311-G-A		Lissencephaly 9 with complex brainstem malformation	Benign (Jan 29, 2024)
1-39084363-C-A			Uncertain significance (Aug 09, 2022)
1-39084381-C-T			Uncertain significance (Feb 27, 2023)
1-39084397-C-T			Uncertain significance (Nov 25, 2023)
1-39084398-G-A			Likely benign (Feb 01, 2024)
1-39084453-C-G			Likely benign (Jan 19, 2023)
1-39084466-C-T			Benign (May 21, 2021)
1-39084538-C-T			Benign (May 12, 2021)
1-39084589-C-T			Benign (May 12, 2021)
1-39230972-G-A			Benign (May 20, 2021)
1-39230975-G-A			Benign (May 12, 2021)
1-39231046-C-A			Benign (May 16, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
MACF1	protein_coding	protein_coding	ENST00000545844	93	405862

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.32e-39	125723	0	25	125748	0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.43	2325	2.84e+3	0.819	0.000160	35716
Missense in Polyphen		835	1175.4	0.71042		14923
Synonymous	-0.627	1077	1.05e+3	1.02	0.0000544	10277
Loss of Function	15.6	18	319	0.0565	0.0000186	3469

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000247	0.000246
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000926	0.0000924
European (Non-Finnish)	0.000141	0.000141
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000681	0.0000653
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Isoform 2: F-actin-binding protein which plays a role in cross-linking actin to other cytoskeletal proteins and also binds to microtubules (PubMed:15265687, PubMed:20937854). Plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex (PubMed:20937854). Acts as a positive regulator of Wnt receptor signaling pathway and is involved in the translocation of AXIN1 and its associated complex (composed of APC, CTNNB1 and GSK3B) from the cytoplasm to the cell membrane (By similarity). Has actin-regulated ATPase activity and is essential for controlling focal adhesions (FAs) assembly and dynamics (By similarity). Interaction with CAMSAP3 at the minus ends of non- centrosomal microtubules tethers microtubules minus-ends to actin filaments, regulating focal adhesion size and cell migration (PubMed:27693509). May play role in delivery of transport vesicles containing GPI-linked proteins from the trans-Golgi network through its interaction with GOLGA4 (PubMed:15265687). Plays a key role in wound healing and epidermal cell migration (By similarity). Required for efficient upward migration of bulge cells in response to wounding and this function is primarily rooted in its ability to coordinate microtubule dynamics and polarize hair follicle stem cells (By similarity). {ECO:0000250|UniProtKB:Q9QXZ0, ECO:0000269|PubMed:15265687, ECO:0000269|PubMed:20937854, ECO:0000269|PubMed:27693509}.
• Pathway: WNT-Ncore;Mesodermal Commitment Pathway (Consensus)

Intolerance Scores

• loftool: 0.458
• rvis_EVS: -3.92
• rvis_percentile_EVS: 0.21

Haploinsufficiency Scores

• pHI: 0.419
• hipred: Y
• hipred_score: 0.667
• ghis: 0.610

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.950

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Macf1
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); respiratory system phenotype; embryo phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: macf1a
• Affected structure: unfertilized egg
• Phenotype tag: abnormal
• Phenotype quality: malformed

Gene ontology

• Biological process: regulation of epithelial cell migration;Wnt signaling pathway;positive regulation of Wnt signaling pathway;regulation of cell migration;regulation of microtubule-based process;wound healing;Golgi to plasma membrane protein transport;intermediate filament cytoskeleton organization;positive regulation of axon extension;regulation of focal adhesion assembly
• Cellular component: cytoplasm;Golgi apparatus;cytoskeleton;microtubule;intermediate filament;plasma membrane;actin cytoskeleton;membrane;ruffle membrane
• Molecular function: RNA binding;actin binding;structural molecule activity;calcium ion binding;protein binding;ATPase activity;cadherin binding;microtubule minus-end binding;actin filament binding