AHCY
protein-codingadenosylhomocysteinase
Gene summary
S-adenosylhomocysteine hydrolase belongs to the adenosylhomocysteinase family. It catalyzes the reversible hydrolysis of S-adenosylhomocysteine (AdoHcy) to adenosine (Ado) and L-homocysteine (Hcy). Thus, it regulates the intracellular S-adenosylhomocysteine (SAH) concentration thought to be important for transmethylation reactions. Deficiency in this protein is one of the different causes of hypermethioninemia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~31.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013404
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013404
Submitter: ClinGen
*AHCY* was first reported in relation to autosomal recessive hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase in 2004 (Baric I, et al., 2004, PMID: 15024124). Main characteristics are psychomotor delay including delayed myelination and myopathy (hypotonia, absent tendon reflexes etc.) from birth, with biochemical abnormalities of marked elevations in plasma SAH, SAM, methionine and creatine kinase accompanied by a significant decrease in the SAM/SAH ratio (however several cases had normal methionine levels at the initial evaluation). At least 13 variants (mostly missense but also nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Biallelic variants in this gene have been reported in at least 12 probands in 12 publications (PMIDs: 15024124, 16736098, 20852937, 22959829, 30121674, 26527160, 26095522, 27848944, 31957987, 35463910, 39512434, 39634240). Variants in this gene segregated with disease in three additional family members. This gene-disease relationship is supported by its biochemical function (PMID: 13641268). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was previously evaluated by the Aminoacidopathy GCEP on 06/29/2020. It was reevaluated on 10/14/2022 with identification of one additional proband in PMID: 31957987. It was agin reevaluated on 12/6/2024 with identification of two additional probands and a C. elegans model in PMIDs: 39512434, 39634240, 38052822. As a result of this reevaluation, the classification moved from Moderate to Definitive.
Inheritance Pattern: AR
Disease ID:MONDO:0013404
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013404
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Neurologic
Intervention: Biochemical
Rationale: Dietary restriction (eg, of methionine) and supplementation (eg, of phosphatidylcholine) may be beneficial in some individuals
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to AHCY variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000687.4. 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 | 1 | 99 | 100 | |||
| missense | 2 | 11 | 122 | 10 | 1 | 146 |
| nonsense | 1 | 3 | 4 | |||
| start loss | 0 | |||||
| frameshift | 2 | 3 | 1 | 6 | ||
| splice donor/acceptor (+/-2bp) | 3 | 6 | 9 | |||
| Total | 5 | 17 | 133 | 109 | 1 | 265 |
Highest pathogenic variant AF is 0.00015434911
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000678.1 | 10 | MANE Select | |
| Ensembl | ENSP00000217426.2 | 10 | MANE Select | |
| RefSeq | NP_001155238.1 | 9 | Standard | |
| RefSeq | NP_001309013.1 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| ahcy | Danio rerio | Structure: hepatocyte Quality: increased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cysteine and methionine metabolism - Homo sapiens (human)
- Thiopurine Pathway, Pharmacokinetics/Pharmacodynamics
- S-Adenosylhomocysteine (SAH) Hydrolase Deficiency
- Methionine Metabolism
- Methionine Adenosyltransferase Deficiency
Biological Process
- sulfur amino acid metabolic process
- response to hypoxia
- chronic inflammatory response to antigenic stimulus
- one-carbon metabolic process
- response to nutrient
Molecular Function
- adenosylhomocysteinase activity
- protein binding
- adenyl nucleotide binding
- identical protein binding
- NAD binding
Cellular Component
- nucleus
- cytosol
- melanosome
- neuron projection
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000217426
- Coding exons
- 10
- Length
- 31535
- Individuals with no LoFs
- 125726
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 22
- Defined
- 125748
- p
- 0.0000875
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.55 | 204 | 277 | 0.737 | 0.0000186 | 2837 |
| Missense (PolyPhen) | 37 | 82.573 | 0.44809 | 1051 | ||
| Synonymous | -0.454 | 122 | 116 | 1.05 | 0.00000864 | 849 |
| Loss of Function | 2.79 | 6 | 19.2 | 0.312 | 9.25e-7 | 224 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000079 | 0.000079 | rare |
| South Asian | 0.00029 | 0.00029 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Adenosylhomocysteine is a competitive inhibitor of S- adenosyl-L-methionine-dependent methyl transferase reactions; therefore adenosylhomocysteinase may play a key role in the control of methylations via regulation of the intracellular concentration of adenosylhomocysteine. {ECO:0000269|PubMed:12590576}.;
- Disease
- DISEASE: Hypermethioninemia with S-adenosylhomocysteine hydrolase deficiency (HMAHCHD) [MIM:613752]: A metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy. {ECO:0000269|PubMed:15024124, ECO:0000269|PubMed:16736098, ECO:0000269|PubMed:19177456, ECO:0000269|PubMed:20852937}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.559
Intolerance Scores
- LoFtool
- 0.245
- RVIS EVS
- -0.07
- RVIS percentile EVS
- 48.69
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 1.00
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |