ASPH

protein-coding

aspartate beta-hydroxylase

Gene summary

This gene is thought to play an important role in calcium homeostasis. The gene is expressed from two promoters and undergoes extensive alternative splicing. The encoded set of proteins share varying amounts of overlap near their N-termini but have substantial variations in their C-terminal domains resulting in distinct functional properties. The longest isoforms (a and f) include a C-terminal Aspartyl/Asparaginyl beta-hydroxylase domain that hydroxylates aspartic acid or asparagine residues in the epidermal growth factor (EGF)-like domains of some proteins, including protein C, coagulation factors VII, IX, and X, and the complement factors C1R and C1S. Other isoforms differ primarily in the C-terminal sequence and lack the hydroxylase domain, and some have been localized to the endoplasmic and sarcoplasmic reticulum. Some of these isoforms are found in complexes with calsequestrin, triadin, and the ryanodine receptor, and have been shown to regulate calcium release from the sarcoplasmic reticulum. Some isoforms have been implicated in metastasis. [provided by RefSeq, Sep 2009]

MANE transcript

NM_004318.4

Inheritance

AR, AD

ClinVar variants

P:29U:113B:48

Top phenotype

Traboulsi syndrome

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr8:61,500,556-61,714,640

External References & Databases

Ensembl (ENSG00000198363)

Transcript & Mutation Effects

hg38 • Region Span ~214.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011106

Submitter: Labcorp Genetics (formerly Invitae)

facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011106

Submitter: PanelApp Australia

malignant hyperthermia of anesthesiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0018493

Submitter: PanelApp Australia

facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011106

Submitter: G2P

facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011106

Submitter: Orphanet

Clinical Genomic Database (CGD)

Traboulsi syndromeAR

Manifestation: Craniofacial; Ophthalmologic

Intervention: Ophthalmologic

Rationale: Early surgical removal of the lens has been reported as necessary in order to preserve visual function by preventing irreversible corneal and trabecular meshwork damage

Refs: 11241487; 23687502; 24768550

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASPH variants in ClinVar

9 Conditions Cataloged

not providedTotal: 90

Inborn genetic diseasesTotal: 90

Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndromeTotal: 27

ASPH-related disorderTotal: 26

not specifiedTotal: 18

Malignant hyperthermia of anesthesiaTotal: 2

Exercise-induced malignant hyperthermiaTotal: 2

EBV-positive nodal T- and NK-cell lymphomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004318.4. 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 clinvar	1 clinvar	32 clinvar	2 clinvar	36
missense		2 clinvar	95 clinvar	11 clinvar	2 clinvar	110
nonsense	6 clinvar	5 clinvar				11
start loss						0
frameshift	4 clinvar	6 clinvar	2 clinvar	1 clinvar		13
splice donor/acceptor (+/-2bp)		5 clinvar	15 clinvar			20
Total	10	19	113	44	4	190

Highest pathogenic variant AF is 0.00005142962

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 382 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004318.4	RefSeq	NP_004309.2	25	MANE Select
ENST00000379454.9	Ensembl	ENSP00000368767.4	25	MANE Select
NM_001164750.2	RefSeq	NP_001158222.1	25	Standard
NM_001164751.2	RefSeq	NP_001158223.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

hypoxia-inducible factor in the cardivascular system
Stimuli-sensing channels
Ion channel transport
Ion homeostasis
Transport of small molecules

Biological Process

muscle contraction
pattern specification process
negative regulation of cell population proliferation
electron transport chain
regulation of protein stability

Molecular Function

peptide-aspartate beta-dioxygenase activity
structural molecule activity
calcium ion binding
protein binding
structural constituent of muscle

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
plasma membrane
integral component of membrane
cortical endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000379454
Coding exons: 25
Length: 214040
Individuals with no LoFs: 125667
Homozygous LoFs: 0
Heterozygous LoFs: 81
Defined: 125748
p: 0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.207	388	400	0.971	0.0000209	4988
Missense (PolyPhen)		114	144.19	0.79064		1694
Synonymous	-0.595	156	147	1.06	0.00000825	1338
Loss of Function	2.59	31	51.0	0.608	0.00000251	614

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00038	0.00037	rare
Latino/Admixed American	0.00053	0.00052	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000059	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00036	0.00036	rare
South Asian	0.00039	0.00036	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 1: specifically hydroxylates an Asp or Asn residue in certain epidermal growth factor-like (EGF) domains of a number of proteins. {ECO:0000269|PubMed:11773073}.;

Recessive Scores

pRec: 0.181

Intolerance Scores

LoFtool: 0.988
RVIS EVS: -1.24
RVIS percentile EVS: 5.52

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.658

Gene Damage Prediction

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