GFAP

protein-coding

glial fibrillary acidic protein, the group of Intermediate filaments Type III

Gene summary

This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

MANE transcript

NM_002055.5

Inheritance

ClinVar variants

P:93U:280B:112

Top phenotype

Alexander disease

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr17:44,903,159-44,916,937

External References & Databases

Ensembl (ENSG00000131095)

Transcript & Mutation Effects

hg38 • Region Span ~13.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Alexander disease type IISUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018210

Submitter: Orphanet

Alexander diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008752

Submitter: Labcorp Genetics (formerly Invitae)

Alexander diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008752

Submitter: PanelApp Australia

Alexander diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008752

Submitter: Genomics England PanelApp

Alexander diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008752

Submitter: ClinGen

The association between autosomal dominant Alexander Disease and variants in GFAP first occurred in 2002 (Li et al., PMID:12175861). Alexander disease, a leukodystrophy characterized by protein aggregates called Rosenthal fibers on brain biopsy, is a primary disorder of astrocytes. The GFAP gene encodes glial fibrillary acidic protein, which is the major intermediate filament protein in astrocytes. The clinical characteristics of Alexander Disease include variable age of onset, from neonatal to adult, and clinical manifestations include developmental delay, seizures, megalencephaly, autonomic dysfunction, and gait abnormalities. Twenty-seven missense variants reported in 27 probands across 7 publications (PMIDs: 12034785, 36088400, 35003479, 27648269, 11567214, 16505300, 15732097) are included in this curation. More evidence exists in the literature, but the maximum required score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is gain-of-function. This gene-disease relationship is supported by experimental evidence, including pathology studies and mouse models (PMIDs: 9466565). In summary, definitive evidence supports the relationship between GFAP and autosomal dominant Alexander Disease, with rigorous and reproducible evidence in research and clinical diagnostic settings. This gene-disease curation based on ClinGen criteria was approved by the Leukodystrophy and Leukoencephalopathy GCEP on the meeting date October 23, 2023. (SOP Version 9).

Alexander diseaseDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008752

Submitter: G2P

Clinical Genomic Database (CGD)

Alexander diseaseAD

Manifestation: 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: 15409268; 13665382; 11138011; 11567214; 12034785; 12447932; 12034796; 14557587; 12975300; 15732097; 15732098; 16505300; 17894839; 17438228; 20301351; 21822933; 21917775; 21987397; 22118268; 22198646; 22488673; 22619055; 23254569; 23364391; 23634874

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GFAP variants in ClinVar

11 Conditions Cataloged

not providedTotal: 471

Alexander diseaseTotal: 220

not specifiedTotal: 76

Inborn genetic diseasesTotal: 54

GFAP-related disorderTotal: 48

Progressive ventriculomegalyTotal: 1

Metachromatic leukodystrophyTotal: 1

ScoliosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002055.5. 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			6 clinvar	57 clinvar	7 clinvar	70
missense	47 clinvar	44 clinvar	242 clinvar	38 clinvar	9 clinvar	380
nonsense			14 clinvar		1 clinvar	15
start loss						0
frameshift		1 clinvar	11 clinvar			12
splice donor/acceptor (+/-2bp)	1 clinvar		7 clinvar			8
Total	48	45	280	95	17	485

Highest pathogenic variant AF is 0.000006578861

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002055.5	RefSeq	NP_002046.1	9	MANE Select
ENST00000588735.3	Ensembl	ENSP00000466598.2	9	MANE Select
NM_001131019.3	RefSeq	NP_001124491.1	8	Standard
NM_001242376.3	RefSeq	NP_001229305.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Jak-STAT signaling pathway - Homo sapiens (human)
Neural Crest Differentiation
Spinal Cord Injury
Signaling by ERBB4
Signal Transduction

Biological Process

response to wounding
positive regulation of Schwann cell proliferation
negative regulation of neuron projection development
astrocyte development
extracellular matrix organization

Molecular Function

integrin binding
structural constituent of cytoskeleton
protein binding
kinase binding
identical protein binding

Cellular Component

cytoplasm
lysosome
cytosol
intermediate filament
myelin sheath

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000586793
Coding exons: 7
Length: 11930
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125748
p: 0.000115

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.929	233	276	0.843	0.0000173	2793
Missense (PolyPhen)		72	105.15	0.68475		1117
Synonymous	2.28	83	114	0.728	0.00000662	915
Loss of Function	1.48	12	19.0	0.633	0.00000105	196

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: GFAP, a class-III intermediate filament, is a cell- specific marker that, during the development of the central nervous system, distinguishes astrocytes from other glial cells.;
Disease: DISEASE: Alexander disease (ALXDRD) [MIM:203450]: A rare disorder of the central nervous system. The most common form affects infants and young children, and is characterized by progressive failure of central myelination, usually leading to death within the first decade. Infants with Alexander disease develop a leukodystrophy with macrocephaly, seizures, and psychomotor retardation. Patients with juvenile or adult forms typically experience ataxia, bulbar signs and spasticity, and a more slowly progressive course. Histologically, Alexander disease is characterized by Rosenthal fibers, homogeneous eosinophilic inclusions in astrocytes. {ECO:0000269|PubMed:11138011, ECO:0000269|PubMed:11567214, ECO:0000269|PubMed:11595337, ECO:0000269|PubMed:12034785, ECO:0000269|PubMed:12034796, ECO:0000269|PubMed:12581808, ECO:0000269|PubMed:12944715, ECO:0000269|PubMed:12975300, ECO:0000269|PubMed:15030911, ECO:0000269|PubMed:15732097, ECO:0000269|PubMed:17043438, ECO:0000269|PubMed:17805552, ECO:0000269|PubMed:17894839, ECO:0000269|PubMed:17934883, ECO:0000269|PubMed:17960815, ECO:0000269|PubMed:18004641, ECO:0000269|PubMed:18079314, ECO:0000269|PubMed:19412928, ECO:0000269|PubMed:20359319, ECO:0000269|PubMed:21917775, ECO:0000269|PubMed:23364391, ECO:0000269|PubMed:23743246, ECO:0000269|PubMed:24742911}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.955

Intolerance Scores

LoFtool: 0.0205
RVIS EVS: 0.62
RVIS percentile EVS: 83.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.527

Gene Damage Prediction

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