POLD4
protein-codingDNA polymerase delta 4, accessory subunit, the group of DNA polymerases
Gene summary
This gene encodes the smallest subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. The encoded protein enhances the activity of DNA polymerase delta and plays a role in fork repair and stabilization through interactions with the DNA helicase Bloom syndrome protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POLD4 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_021173.5. 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 | 2 | 1 | 3 | |||
| missense | 11 | 11 | ||||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 2 | 2 | ||||
| Total | 0 | 0 | 15 | 1 | 0 | 16 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_066996.3 | 4 | MANE Select | |
| Ensembl | ENSP00000311368.3 | 4 | MANE Select | |
| RefSeq | NP_001243799.1 | 3 | Standard | |
| Ensembl | ENSP00000481251.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Nucleotide excision repair - Homo sapiens (human)
- Pyrimidine metabolism - Homo sapiens (human)
- Base excision repair - Homo sapiens (human)
- HTLV-I infection - Homo sapiens (human)
- Mismatch repair - Homo sapiens (human)
Biological Process
- telomere maintenance
- DNA-dependent DNA replication
- transcription-coupled nucleotide-excision repair
- nucleotide-excision repair, DNA incision, 5'-to lesion
- nucleotide-excision repair, DNA gap filling
Molecular Function
- DNA-directed DNA polymerase activity
- protein binding
Cellular Component
- nucleus
- nucleoplasm
- nucleolus
- mitochondrion
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000312419
- Coding exons
- 4
- Length
- 6196
- Individuals with no LoFs
- 125541
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 16
- Defined
- 125557
- p
- 0.0000637
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.427 | 51 | 60.3 | 0.845 | 0.00000321 | 665 |
| Missense (PolyPhen) | 16 | 20.675 | 0.7739 | 220 | ||
| Synonymous | 0.218 | 23 | 24.4 | 0.944 | 0.00000122 | 202 |
| Loss of Function | 1.48 | 2 | 5.85 | 0.342 | 2.49e-7 | 68 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00033 | 0.00030 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000071 | 0.000062 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair. Within this complex, increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3' to 5' exonuclease activity (PubMed:16510448, PubMed:19074196, PubMed:20334433). Pol-delta4 participates in Okazaki fragment processing, through both the short flap pathway, as well as a nick translation system (PubMed:24035200). Under conditions of DNA replication stress, required for the repair of broken replication forks through break- induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb (PubMed:24310611). Involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites (PubMed:19074196). Its degradation in response to DNA damage is required for the inhibition of fork progression and cell survival (PubMed:24022480). {ECO:0000269|PubMed:16510448, ECO:0000269|PubMed:19074196, ECO:0000269|PubMed:20334433, ECO:0000269|PubMed:24022480, ECO:0000269|PubMed:24035200, ECO:0000269|PubMed:24310611}.;
Recessive Scores
- pRec
- 0.0898
Intolerance Scores
- LoFtool
- 0.636
- RVIS EVS
- 0.19
- RVIS percentile EVS
- 66.57
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |