FA2H

fatty acid 2-hydroxylase, the group of Fatty acid hydroxylase domain containing

Basic information

Region (hg38): 16:74712954-74774831

Previous symbols: [ "FAXDC1", "SPG35" ]

Links

ENSG00000103089 ∙ NCBI:79152 ∙ OMIM:611026 ∙ HGNC:21197 ∙ Uniprot:Q7L5A8 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 35 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 35 (Supportive), mode of inheritance: AR
• hereditary spastic paraplegia 35 (Definitive), mode of inheritance: AR
• hereditary spastic paraplegia 35 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paraplegia 35, autosomal recessive, with or without neurodegeneration	AR	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	Biochemical; Neurologic	18463364; 19068277; 20104589; 20853438; 22146942; 22925154; 23745665; 24359114

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FA2H gene.

• Spastic paraplegia (202 variants)
• Hereditary spastic paraplegia 35 (111 variants)
• not provided (82 variants)
• Hereditary spastic paraplegia (26 variants)
• not specified (24 variants)
• Inborn genetic diseases (16 variants)
• Neurodegeneration with brain iron accumulation (3 variants)
• Spastic ataxia (1 variants)
• See cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FA2H 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			6	50	6	62
missense	5	9	92	8	1	115
nonsense	8	2				10
start loss	2					2
frameshift	9	3	1			13
inframe indel	1		3			4
splice donor/acceptor (+/-2bp)		5				5
splice region	1		6	3	1	11
non coding			22	34	22	78
Total	25	19	124	92	29

Highest pathogenic variant AF is 0.0000132

Variants in FA2H

This is a list of pathogenic ClinVar variants found in the FA2H region.

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

Position	Type	Phenotype	Significance	ClinVar
16-74713002-T-C		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713059-T-G		Hereditary spastic paraplegia 35	Benign (Jan 13, 2018)
16-74713061-C-T		Hereditary spastic paraplegia 35	Benign (Jan 13, 2018)
16-74713116-C-T		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713126-G-C		Hereditary spastic paraplegia 35	Benign (Jan 12, 2018)
16-74713232-G-A		Hereditary spastic paraplegia 35	Likely benign (Jan 12, 2018)
16-74713279-G-T		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713303-A-T		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713305-C-A		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713369-G-C		Hereditary spastic paraplegia 35	Likely benign (Jan 13, 2018)
16-74713377-G-A		Hereditary spastic paraplegia 35	Likely benign (Jan 13, 2018)
16-74713407-C-T		Hereditary spastic paraplegia 35	Likely benign (Jan 13, 2018)
16-74713418-G-T		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713537-C-T		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713538-G-A		Hereditary spastic paraplegia 35	Uncertain significance (Jan 12, 2018)
16-74713544-A-C		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713553-C-G		Hereditary spastic paraplegia 35	Benign (Jan 13, 2018)
16-74713670-C-T		Hereditary spastic paraplegia 35	Likely benign (Jan 13, 2018)
16-74713684-G-C		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713685-C-A		Hereditary spastic paraplegia 35	Uncertain significance (Jan 12, 2018)
16-74713743-G-A		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713786-A-T		Hereditary spastic paraplegia 35	Benign (Jan 13, 2018)
16-74713799-G-A		Hereditary spastic paraplegia 35	Uncertain significance (Jan 13, 2018)
16-74713888-C-T		Hereditary spastic paraplegia 35	Uncertain significance (Jan 12, 2018)
16-74713907-C-G		Hereditary spastic paraplegia 35	Benign (Jul 17, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FA2H	protein_coding	protein_coding	ENST00000219368	7	61877

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.147	0.853	125736	0	11	125747	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.456	179	197	0.909	0.0000112	2378
Missense in Polyphen		51	68.959	0.73957		834
Synonymous	-0.522	94	87.8	1.07	0.00000573	734
Loss of Function	2.96	5	18.9	0.265	0.00000107	190

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000906	0.0000906
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000529	0.0000527
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Required for alpha-hydroxylation of free fatty acids and the formation of alpha-hydroxylated sphingolipids. {ECO:0000269|PubMed:15337768, ECO:0000269|PubMed:17355976}.
• Disease: DISEASE: Spastic paraplegia 35, autosomal recessive (SPG35) [MIM:612319]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG35 is a complicated form characterized by childhood onset of gait difficulties. It has a rapid progression and many patients become wheelchair-bound as young adults. Patients manifest cognitive decline associated with leukodystrophy. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur. {ECO:0000269|PubMed:19068277, ECO:0000269|PubMed:20104589, ECO:0000269|PubMed:20853438}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Metabolism of lipids;Metabolism;fatty acid α-oxidation III;Sphingolipid de novo biosynthesis;Sphingolipid metabolism (Consensus)

Recessive Scores

• pRec: 0.131

Intolerance Scores

• loftool: 0.0542
• rvis_EVS: -0.25
• rvis_percentile_EVS: 35.99

Haploinsufficiency Scores

• pHI: 0.262
• hipred: Y
• hipred_score: 0.749
• ghis: 0.516

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.250

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fa2h
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); vision/eye 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); endocrine/exocrine gland phenotype; 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); homeostasis/metabolism phenotype

Gene ontology

• Biological process: sebaceous gland cell differentiation;fatty acid metabolic process;fatty acid biosynthetic process;glucosylceramide biosynthetic process;galactosylceramide biosynthetic process;sphingolipid biosynthetic process;lipid modification;central nervous system myelin maintenance;peripheral nervous system myelin maintenance;regulation of cell population proliferation;regulation of hair cycle;plasma membrane raft organization;ceramide biosynthetic process;oxidation-reduction process;establishment of skin barrier
• Cellular component: endoplasmic reticulum;endoplasmic reticulum membrane;membrane;integral component of membrane;organelle membrane
• Molecular function: iron ion binding;heme binding;fatty acid alpha-hydroxylase activity