SERPINH1

protein-coding

serpin family H member 1, the group of Serpin peptidase inhibitors

Gene summary

This gene encodes a member of the serpin superfamily of serine proteinase inhibitors. The encoded protein is localized to the endoplasmic reticulum and plays a role in collagen biosynthesis as a collagen-specific molecular chaperone. Autoantibodies to the encoded protein have been found in patients with rheumatoid arthritis. Expression of this gene may be a marker for cancer, and nucleotide polymorphisms in this gene may be associated with preterm birth caused by preterm premature rupture of membranes. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the short arm of chromosome 9. [provided by RefSeq, May 2011]

Previous symbols:

CBP1
CBP2
SERPINH2

MANE transcript

NM_001235.5

Inheritance

AR, AD

ClinVar variants

P:12U:145B:84

Top phenotype

Osteogenesis imperfecta, type X

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr11:75,562,056-75,572,783

External References & Databases

Ensembl (ENSG00000149257)

Transcript & Mutation Effects

hg38 • Region Span ~10.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

osteogenesis imperfecta type 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013459

Submitter: Labcorp Genetics (formerly Invitae)

osteogenesis imperfecta type 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013459

Submitter: Ambry Genetics

osteogenesis imperfecta type 3SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009804

Submitter: Orphanet

osteogenesis imperfecta type 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013459

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Osteogenesis imperfecta, type XAR

Manifestation: Craniofacial; Dental; Musculoskeletal; Ophthalmologic; Renal

Intervention: General

Rationale: 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

Refs: 20188343

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SERPINH1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 200

Inborn genetic diseasesTotal: 69

Osteogenesis imperfecta type 10Total: 39

not specifiedTotal: 18

SERPINH1-related disorderTotal: 13

Osteogenesis imperfectaTotal: 7

Preterm premature rupture of membranesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001235.5. 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			3 clinvar	71 clinvar	1 clinvar	75
missense	1 clinvar	2 clinvar	138 clinvar	12 clinvar		153
nonsense	3 clinvar		1 clinvar			4
start loss			1 clinvar			1
frameshift	4 clinvar	1 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	9	3	145	83	1	241

Highest pathogenic variant AF is 0.000023265999

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001235.5	RefSeq	NP_001226.2	4	MANE Select
ENST00000358171.8	Ensembl	ENSP00000350894.4	4	MANE Select
NM_001207014.3	RefSeq	NP_001193943.1	4	Standard
NM_001440311.1	RefSeq	NP_001427240.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
serpinh1b	Danio rerio	Structure: regenerating fin Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

serpinh1b

Danio rerio

Structure: regenerating fin

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cellular response to heat stress
Endochondral Ossification
HSF1 activation
Attenuation phase
HSF1-dependent transactivation

Biological Process

chondrocyte development involved in endochondral bone morphogenesis
response to unfolded protein
negative regulation of endopeptidase activity
collagen fibril organization
collagen biosynthetic process

Molecular Function

RNA binding
serine-type endopeptidase inhibitor activity
collagen binding
unfolded protein binding

Cellular Component

extracellular space
endoplasmic reticulum
endoplasmic reticulum lumen
endoplasmic reticulum-Golgi intermediate compartment
membrane raft

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000524558
Coding exons: 4
Length: 10728
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 125747
p: 0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0482	269	271	0.992	0.0000201	2699
Missense (PolyPhen)		88	103	0.85438		1116
Synonymous	-0.783	140	129	1.09	0.0000111	844
Loss of Function	2.25	5	14.1	0.355	8.01e-7	155

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000072	0.000062	rare
Latino/Admixed American	0.00020	0.00012	rare
Ashkenazi Jewish	0.00020	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000082	0.000079	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds specifically to collagen. Could be involved as a chaperone in the biosynthetic pathway of collagen.;
Disease: DISEASE: Osteogenesis imperfecta 10 (OI10) [MIM:613848]: A form of osteogenesis imperfecta, a connective tissue disorder characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI10 is an autosomal recessive form characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclerae. {ECO:0000269|PubMed:20188343}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.396

Intolerance Scores

LoFtool: 0.120
RVIS EVS: -0.6
RVIS percentile EVS: 17.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.712

Gene Damage Prediction

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