HMBS

hydroxymethylbilane synthase

Basic information

Region (hg38): 11:119084865-119093834

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

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hydroxymethylbilane synthase deficiency; Porphyria, acute intermittent	AD/AR	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 effective	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
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 (410 variants)
• Acute intermittent porphyria (91 variants)
• not specified (12 variants)
• HMBS-related condition (3 variants)
• Porphyria, acute intermittent, nonerythroid variant (3 variants)
• Inborn genetic diseases (3 variants)
• Anxiety (1 variants)
• Mood changes;Abdominal pain;Visual loss;Fever;Vomiting (1 variants)
• Congenital disorder of glycosylation (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.

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			3	54	4	61
missense	16	21	126	5		168
nonsense	11	1				12
start loss			1			1
frameshift	25	5	1			31
inframe indel	1		2			3
splice donor/acceptor (+/-2bp)	28	2	2			32
splice region		3	22	13	1	39
non coding	5		12	46	18	81
Total	86	29	147	105	22

Highest pathogenic variant AF is 0.0000197

Variants in HMBS

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

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

Position	Type	Phenotype	Significance	ClinVar
11-119084878-CG-C		Porphyria, acute intermittent, nonerythroid variant	Pathogenic (Sep 01, 2000)
11-119084931-C-T			Benign (Oct 22, 2019)
11-119084969-C-T		Acute intermittent porphyria	Benign (Jan 12, 2018)
11-119085006-A-C		Acute intermittent porphyria • not specified	Conflicting classifications of pathogenicity (Mar 01, 2024)
11-119085034-A-G		Porphyria, acute intermittent, nonerythroid variant	Uncertain significance (Jul 06, 2022)
11-119085037-T-C			Uncertain significance (Jul 05, 2022)
11-119085046-G-A		Acute intermittent porphyria	Uncertain significance (Dec 07, 2018)
11-119085055-G-A		Inborn genetic diseases	Uncertain significance (Sep 15, 2021)
11-119085058-G-A			Uncertain significance (Apr 20, 2022)
11-119085059-C-A		not specified • Acute intermittent porphyria	Conflicting classifications of pathogenicity (Sep 19, 2022)
11-119085060-A-G			Likely benign (Apr 16, 2023)
11-119085062-C-T			Uncertain significance (Oct 21, 2022)
11-119085063-G-A			Likely benign (Jan 04, 2024)
11-119085064-G-A			Likely benign (Jan 29, 2024)
11-119085065-C-T			Uncertain significance (Mar 19, 2023)
11-119085066-G-C			Uncertain significance (Dec 20, 2018)
11-119085067-G-A		Porphyria, acute intermittent, nonerythroid variant	Pathogenic (Mar 29, 2022)
11-119085067-G-T		Porphyria, acute intermittent, nonerythroid variant	Pathogenic (Jun 12, 2022)
11-119085068-T-G			Pathogenic (Jul 02, 2021)
11-119085074-C-G			Uncertain significance (Nov 12, 2022)
11-119085075-T-C			Likely benign (Jul 08, 2022)
11-119085076-G-C			Likely benign (Nov 10, 2023)
11-119085081-G-A		not specified	Likely benign (Dec 31, 2023)
11-119085084-G-A		not specified	Likely benign (Mar 11, 2024)
11-119085086-C-G			Benign (Jan 31, 2024)

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
0.949	0.0512	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

Haploinsufficiency Scores

• pHI: 0.380
• hipred: Y
• hipred_score: 0.654
• ghis: 0.413

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

Mouse Genome Informatics

• Gene name: Hmbs
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); normal 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); 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); renal/urinary system phenotype; muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

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