GeneBe

PDCD6IP

protein-coding

programmed cell death 6 interacting protein

Gene summary

This gene encodes a protein that functions within the ESCRT pathway in the abscission stage of cytokinesis, in intralumenal endosomal vesicle formation, and in enveloped virus budding. Studies using mouse cells have shown that overexpression of this protein can block apoptosis. In addition, the product of this gene binds to the product of the PDCD6 gene, a protein required for apoptosis, in a calcium-dependent manner. This gene product also binds to endophilins, proteins that regulate membrane shape during endocytosis. Overexpression of this gene product and endophilins results in cytoplasmic vacuolization, which may be partly responsible for the protection against cell death. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. Related pseudogenes have been identified on chromosome 15. [provided by RefSeq, Jan 2012]

MANE transcript

NM_013374.6

Inheritance

AR

ClinVar variants

P:1U:108B:10

Top phenotype

Microcephaly 29, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr3:33,798,571-33,869,707

External References & Databases

Ensembl (ENSG00000170248)NCBI Gene (10015)OMIM (608074)HGNC:8766GenCCUniProt (Q8WUM4)AlphaFoldClinVar (PDCD6IP)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~71.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 29, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0031060

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly 29, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0031060

Submitter: LiferaOmics

Genetic evidence – Published PMID: 32286682 – Reports two affected brothers from one consanguineous family. One proband counted for case-level; affected sibling counted under segregation. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = 1.0 Segregation (affected sibling; conservative assignment) = 0.5; Case-control = 0 Family 1 total = 1.5 PMID: 32286682 total = 1.5 PMID: 40897677– Reports one unrelated individual. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = 1.0; Segregation = 0; Case-control =0 Family 2 total = 1.0 PMID: 40897677 total = 1.0 Published genetic evidence total = 2.5 / 12 Genetic evidence – Our Case Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous; consanguinity −0.5 applied) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Our Cases Total = 1.0 / 12 Updated Total Genetic Evidence (Published + Our Cases) Published genetic evidence: 2.5 Our additional cases: 1.0 Updated genetic total = 3.5 / 12 Experimental Evidence – Published Evidence supporting biological plausibility: PDCD6IP (ALIX) regulates the ESCRT complex involved in membrane remodeling, cytokinesis, and intracellular trafficking — mechanisms relevant to neural progenitor proliferation and brain development. Gene function / Expression / biological plausibility = 1.0 Animal/model evidence: Pdcd6ip (Alix) knockout mice demonstrate reduced brain growth consistent with a microcephaly mechanism. Animal/model evidence (brain growth relevance) = 2.5 Experimental evidence total = 3.5 / 6 Updated Overall Score Genetic evidence = 3.5 Experimental evidence = 3.5 Updated total = 7.0 / 18

microcephaly 29, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0031060

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Microcephaly 29, primary, autosomal recessiveAR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

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: 32286682Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDCD6IP variants in ClinVar

3 Conditions Cataloged
not specifiedTotal: 102
not providedTotal: 7
Microcephaly 29, primary, autosomal recessiveTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013374.6. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
2
clinvar
2
clinvar
 8
missense
100
clinvar
4
clinvar
2
clinvar
 106
nonsense
0
start loss
0
frameshift
1
clinvar
1
clinvar
 2
splice donor/acceptor (+/-2bp)
3
clinvar
 3
Total1010864119
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 43 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_013374.6RefSeqNP_037506.218MANE Select
ENST00000307296.8EnsemblENSP00000307387.318MANE Select
NM_001162429.3RefSeqNP_001155901.118Standard
NM_001256192.2RefSeqNP_001243121.16Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Endocytosis - Homo sapiens (human)
  • Disease
  • Budding and maturation of HIV virion
  • Late Phase of HIV Life Cycle
  • HIV Life Cycle

Biological Process

  • mitotic cytokinesis
  • actomyosin contractile ring assembly
  • apoptotic process
  • nucleus organization
  • mitotic metaphase plate congression

Molecular Function

  • protein binding
  • proteinase activated receptor binding
  • protein homodimerization activity
  • calcium-dependent protein binding

Cellular Component

  • immunological synapse
  • microtubule organizing center
  • cytosol
  • bicellular tight junction
  • focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000457054
Coding exons
18
Length
71351
Individuals with no LoFs
125735
Homozygous LoFs
0
Heterozygous LoFs
9
Defined
125744
p
0.0000358
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.9763934510.8710.00002205656
Missense (PolyPhen)72115.580.622931478
Synonymous-0.2391741701.020.000008711694
Loss of Function4.85943.60.2070.00000210571

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000120.00011rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000450.000044rare
South Asian00.0absent
Other0.000200.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Multifunctional protein involved in endocytosis, multivesicular body biogenesis, membrane repair, cytokinesis, apoptosis and maintenance of tight junction integrity. Class E VPS protein involved in concentration and sorting of cargo proteins of the multivesicular body (MVB) for incorporation into intralumenal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome. Binds to the phospholipid lysobisphosphatidic acid (LBPA) which is abundant in MVBs internal membranes. The MVB pathway requires the sequential function of ESCRT-O, -I,-II and -III complexes (PubMed:14739459). The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis (PubMed:17853893, PubMed:17556548). Adapter for a subset of ESCRT-III proteins, such as CHMP4, to function at distinct membranes. Required for completion of cytokinesis (PubMed:17853893, PubMed:17556548, PubMed:18641129). May play a role in the regulation of both apoptosis and cell proliferation. Regulates exosome biogenesis in concert with SDC1/4 and SDCBP (PubMed:22660413). By interacting with F-actin, PARD3 and TJP1 secures the proper assembly and positioning of actomyosin-tight junction complex at the apical sides of adjacent epithelial cells that defines a spatial membrane domain essential for the maintenance of epithelial cell polarity and barrier (By similarity). {ECO:0000250|UniProtKB:Q9WU78, ECO:0000269|PubMed:14739459, ECO:0000269|PubMed:17556548, ECO:0000269|PubMed:17853893, ECO:0000269|PubMed:18641129, ECO:0000269|PubMed:22660413}.;

Recessive Scores

pRec
0.125

Intolerance Scores

LoFtool
0.582
RVIS EVS
-0.31
RVIS percentile EVS
32.23

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
H
Indispensability pred.
E
Indispensability score
0.921

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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