CSTA

protein-coding

cystatin A, the group of Cystatins, type 1

Gene summary

The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins, and kininogens. This gene encodes a stefin that functions as a cysteine protease inhibitor, forming tight complexes with papain and the cathepsins B, H, and L. The protein is one of the precursor proteins of cornified cell envelope in keratinocytes and plays a role in epidermal development and maintenance. Stefins have been proposed as prognostic and diagnostic tools for cancer. [provided by RefSeq, Jul 2008]

Previous symbols:

STF1
STFA

MANE transcript

NM_005213.4

Inheritance

ClinVar variants

P:6U:15B:2

Top phenotype

Peeling skin syndrome 4

gnomAD constraint

pLI —, LoF o/e 1.35

Max pathogenic AF

—

Genomic locus

chr3:122,325,248-122,341,969

External References & Databases

Ensembl (ENSG00000121552)

Transcript & Mutation Effects

hg38 • Region Span ~16.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

peeling skin syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011937

Submitter: Genomics England PanelApp

peeling skin syndrome 4MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011937

Submitter: Ambry Genetics

acral peeling skin syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012345

Submitter: Orphanet

exfoliative ichthyosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017339

Submitter: Orphanet

peeling skin syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011937

Submitter: Labcorp Genetics (formerly Invitae)

peeling skin syndrome 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011937

Submitter: G2P

Clinical Genomic Database (CGD)

Peeling skin syndrome 4AR

Manifestation: Dermatologic

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: 21944047; 25400170

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CSTA variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 13

not providedTotal: 6

Peeling skin syndrome 4Total: 5

CSTA-related disorderTotal: 3

not specifiedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005213.4. 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						0
missense			14 clinvar	1 clinvar	1 clinvar	16
nonsense	2 clinvar	2 clinvar	1 clinvar			5
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)	1 clinvar					1
Total	3	3	15	1	1	23

Highest pathogenic variant AF is 0.000028507755

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005213.4	RefSeq	NP_005204.1	3	MANE Select
ENST00000264474.4	Ensembl	ENSP00000264474.3	3	MANE Select
ENST00000479204.1	Ensembl	ENSP00000418891.1	2	Standard
ENST00000479204.2	Ensembl	ENSP00000418891.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Keratinization
Developmental Biology
Formation of the cornified envelope

Biological Process

negative regulation of peptidase activity
negative regulation of endopeptidase activity
peptide cross-linking
keratinocyte differentiation
negative regulation of proteolysis

Molecular Function

protease binding
cysteine-type endopeptidase inhibitor activity
structural molecule activity
protein binding, bridging

Cellular Component

cornified envelope
extracellular space
nucleus
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264474
Coding exons: 3
Length: 16729
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125745
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0715	50	51.4	0.972	0.00000253	632
Missense (PolyPhen)		16	19.456	0.82236		249
Synonymous	-0.322	22	20.2	1.09	0.00000122	176
Loss of Function	-0.626	5	3.70	1.35	1.56e-7	45

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This is an intracellular thiol proteinase inhibitor. Has an important role in desmosome-mediated cell-cell adhesion in the lower levels of the epidermis. {ECO:0000269|PubMed:21944047}.;

Recessive Scores

pRec: 0.161

Intolerance Scores

LoFtool: 0.764
RVIS EVS: 0.33
RVIS percentile EVS: 73.11

Essentials

Essential (CRISPR): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.671

Gene Damage Prediction

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