HMBS

hydroxymethylbilane synthase

Basic information

Region (hg38): 11:119084866-119093834

Previous symbols: [ "PBGD", "UPS", "PORC" ]

Links

ENSG00000256269 ∙ NCBI:3145 ∙ OMIM:609806 ∙ HGNC:4982 ∙ Uniprot:P08397 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• acute intermittent porphyria (Strong), mode of inheritance: AD
• acute intermittent porphyria (Definitive), mode of inheritance: Semidominant
• acute intermittent porphyria (Strong), mode of inheritance: AD
• acute intermittent porphyria (Supportive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Porphyria, acute intermittent; Encephalopathy, porphyria-related; Leukoencephalopathy, porphyria-related	AD	Biochemical; Endocrine; Gastrointestinal; Pharmacogenomic; Oncologic	Attacks may be precipitated by porphyrinogenic agents (eg, barbiturates, sulfonamides), which, along with other exacerbating factors (eg, alcohol, infection) should be avoided; Endocrinological interventions may be beneficial in affected females; Acute attacks can be managed with supportive care (including TPN if necessary), and with medical treatment (eg, hematin); Surveillance for complications (eg, hepatocellular carcinoma) is indicated; Liver transplant has been reported as beneficial	Biochemical; Endocrine; Gastrointestinal; Hematologic; Neurologic; Oncologic	13354248; 14198005; 4907358; 1106284; 329053; 665312; 87561; 449661; 7251856; 7258864; 6878621; 6433194; 2864531; 3724815; 3595653; 2789372; 2563167; 2246851; 2246852; 1577472; 7866402; 9199558; 10343207; 9860299; 10453740; 11071386; 14970743; 15001330; 15534187; 16211556; 17298217; 18627369; 18647325; 19460837; 19656452; 20301372; 22748422; 27558376; 34089223
Homozygosity/compound heterozygosity results in a distinct and much more severe phenotype

ClinVar

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

• not_provided (628 variants)
• Acute_intermittent_porphyria (118 variants)
• not_specified (24 variants)
• HMBS-related_disorder (15 variants)
• Inborn_genetic_diseases (14 variants)
• Encephalopathy,_porphyria-related (9 variants)
• Leukoencephalopathy,_porphyria-related (7 variants)
• Porphyria,_acute_intermittent,_nonerythroid_variant (4 variants)
• Abdominal_pain (2 variants)
• Anxiety (2 variants)
• Acute_episodes_of_neuropathic_symptoms (1 variants)
• Fever (1 variants)
• Hereditary_ataxia (1 variants)
• Emotional_lability (1 variants)
• Visual_loss (1 variants)
• Vomiting (1 variants)
• Elevated_urinary_delta-aminolevulinic_acid (1 variants)
• Abnormal_circulating_porphyrin_concentration (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HMBS gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000190.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	99	3	111
missense	25	33	201	9		268
nonsense	14	4				18
start loss			1			1
frameshift	49	12	1			62
splice donor/acceptor (+/-2bp)	43	7	3			53
Total	131	56	215	108	3

Highest pathogenic variant AF is 0.00018817658

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HMBS	protein_coding	protein_coding	ENST00000278715	14	8684

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
		125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.643	179	205	0.874	0.0000122	2347
Missense in Polyphen		56	85.53	0.65474		966
Synonymous	-1.23	93	79.1	1.18	0.00000469	734
Loss of Function	3.82	3	22.6	0.133	0.00000125	254

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000148	0.000148
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000264	0.0000264
Middle Eastern	0.0000544	0.0000544
South Asian	0.000232	0.000229
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Tetrapolymerization of the monopyrrole PBG into the hydroxymethylbilane pre-uroporphyrinogen in several discrete steps.
• Pathway: Porphyrin and chlorophyll metabolism - Homo sapiens (human);Hereditary Coproporphyria (HCP);Porphyria Variegata (PV);Congenital Erythropoietic Porphyria (CEP) or Gunther Disease;Acute Intermittent Porphyria;Porphyrin Metabolism;Heme Biosynthesis;hemoglobins chaperone;Heme biosynthesis;Metabolism of porphyrins;Metabolism;Porphyrin metabolism;tetrapyrrole biosynthesis;heme biosynthesis (Consensus)

Recessive Scores

• pRec: 0.691

Intolerance Scores

• loftool: 0.0251
• rvis_EVS: -0.34
• rvis_percentile_EVS: 30.37

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.969

Gene Damage Prediction

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

Gene ontology

• Biological process: protoporphyrinogen IX biosynthetic process;heme biosynthetic process;peptidyl-pyrromethane cofactor linkage
• Cellular component: cytoplasm;cytosol
• Molecular function: hydroxymethylbilane synthase activity