PDIA6

protein-coding

protein disulfide isomerase family A member 6, the group of Protein disulfide isomerases|Thioredoxin domain containing

Gene summary

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, two catalytically active thioredoxin (TRX) domains, a TRX-like domain, and a C-terminal ER-retention sequence. This protein inhibits the aggregation of misfolded proteins and exhibits both isomerase and chaperone activity. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

Previous symbols:

TXNDC7

MANE transcript

NM_005742.4

Inheritance

ClinVar variants

P:3U:71B:1

Top phenotype

multiple congenital anomalies/dysmorphic syndrome

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr2:10,783,391-10,837,977

External References & Databases

Ensembl (ENSG00000143870)

Transcript & Mutation Effects

hg38 • Region Span ~54.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple congenital anomalies/dysmorphic syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0019042

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDIA6 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 63

not providedTotal: 4

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005742.4. 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		2
missense			62 clinvar			62
nonsense	1 clinvar		1 clinvar			2
start loss						0
frameshift		1 clinvar	2 clinvar			3
splice donor/acceptor (+/-2bp)		1 clinvar	5 clinvar			6
Total	1	2	71	1	0	75

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005742.4	RefSeq	NP_005733.1	13	MANE Select
ENST00000272227.8	Ensembl	ENSP00000272227.4	13	MANE Select
NM_001282704.2	RefSeq	NP_001269633.1	14	Standard
NM_001282705.2	RefSeq	NP_001269634.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
Ibuprofen Action Pathway
Phenytoin (Antiarrhythmic) Action Pathway
Ibuprofen Metabolism Pathway
Morphine Metabolism Pathway

Biological Process

protein folding
IRE1-mediated unfolded protein response
post-translational protein modification
cellular protein metabolic process
cell redox homeostasis

Molecular Function

protein disulfide isomerase activity
protein binding
peptide disulfide oxidoreductase activity

Cellular Component

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

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000272227
Coding exons: 13
Length: 54587
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125747
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.704	219	250	0.875	0.0000143	2854
Missense (PolyPhen)		56	73.753	0.75929		909
Synonymous	1.09	84	97.7	0.860	0.00000627	843
Loss of Function	3.53	6	25.1	0.239	0.00000122	299

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00010	0.000097	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function as a chaperone that inhibits aggregation of misfolded proteins (PubMed:12204115). Negatively regulates the unfolded protein response (UPR) through binding to UPR sensors such as ERN1, which in turn inactivates ERN1 signaling (PubMed:24508390). May also regulate the UPR via the EIF2AK3 UPR sensor (PubMed:24508390). Plays a role in platelet aggregation and activation by agonists such as convulxin, collagen and thrombin (PubMed:15466936). {ECO:0000269|PubMed:12204115, ECO:0000269|PubMed:15466936, ECO:0000269|PubMed:24508390}.;

Recessive Scores

pRec: 0.0973

Intolerance Scores

LoFtool: 0.752
RVIS EVS: -0.69
RVIS percentile EVS: 15.12

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.783

Gene Damage Prediction

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