GeneBe

PAX8

protein-coding

paired box 8, the group of PRD class homeoboxes and pseudogenes|Paired boxes

Gene summary

This gene encodes a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins that contain a paired box domain, an octapeptide, and a paired-type homeodomain. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

MANE transcript

NM_003466.4

Inheritance

AD

ClinVar variants

P:28U:106B:47

Top phenotype

Hypothyroidism, congenital, nongoitrous 2

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr2:113,215,997-113,278,921

External References & Databases

Ensembl (ENSG00000125618)NCBI Gene (7849)OMIM (167415)HGNC:8622GenCCUniProt (Q06710)AlphaFoldClinVar (PAX8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~62.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hypothyroidism, congenital, nongoitrous, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024264

Submitter: Labcorp Genetics (formerly Invitae)

athyreosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019855

Submitter: Orphanet

thyroid hypoplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019861

Submitter: Orphanet

hypothyroidism, congenital, nongoitrous, 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0024264

Submitter: G2P

hypothyroidism, congenital, nongoitrous, 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0024264

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Hypothyroidism, congenital, nongoitrous 2AD

Manifestation: Endocrine; Renal

Intervention: Endocrine

Rationale: The untreated condition can result in severe neurological damage, and recognition can allow early medical treatment with thyroid hormone replacement can prevent such sequelae

Comments: Individuals with genitourinary anomalies possibly associated with the variant have been described

Refs: 9590296; 11502839; 11232006; 15356023; 15718293; 20718765; 20857061; 21450989; 21689132; 21976720; 22898500; 23647375Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PAX8 variants in ClinVar

7 Conditions Cataloged
Inborn genetic diseasesTotal: 74
Hypothyroidism, congenital, nongoitrous, 2Total: 71
not providedTotal: 67
not specifiedTotal: 27
PAX8-related disorderTotal: 13
Congenital hypothyroidismTotal: 5
Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003466.4. 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.

EffectPLPVUSLBBSum
synonymous
8
clinvar
29
clinvar
3
clinvar
 40
missense
8
clinvar
7
clinvar
90
clinvar
15
clinvar
 120
nonsense
2
clinvar
4
clinvar
 6
start loss
0
frameshift
1
clinvar
4
clinvar
2
clinvar
 7
splice donor/acceptor (+/-2bp)
1
clinvar
1
clinvar
6
clinvar
 8
Total1216106443181

Highest pathogenic variant AF is 0.000006195495

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 37 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003466.4RefSeqNP_003457.111MANE Select
ENST00000429538.8EnsemblENSP00000395498.311MANE Select
NM_013952.4RefSeqNP_039246.110Standard
NM_013953.4RefSeqNP_039247.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
pax8Danio rerio

Structure: lateral crista

Quality: physical object quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Thyroid hormone synthesis - Homo sapiens (human)
  • Pathways in cancer - Homo sapiens (human)
  • Transcriptional misregulation in cancer - Homo sapiens (human)
  • Thyroid cancer - Homo sapiens (human)
  • Human Thyroid Stimulating Hormone (TSH) signaling pathway

Biological Process

  • urogenital system development
  • branching involved in ureteric bud morphogenesis
  • kidney development
  • mesonephros development
  • ventricular septum development

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • DNA-binding transcription factor activity, RNA polymerase II-specific
  • DNA-binding transcription activator activity, RNA polymerase II-specific
  • DNA binding
  • DNA-binding transcription factor activity

Cellular Component

  • nucleus
  • nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000429538
Coding exons
11
Length
62954
Individuals with no LoFs
124862
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
124866
p
0.0000160
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.7852392760.8670.00001742877
Missense (PolyPhen)70112.370.622951117
Synonymous-0.8341301181.100.00000827914
Loss of Function4.32123.70.04220.00000138247

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish0.0000990.000099rare
East Asian00.0absent
Finnish0.0000470.000046rare
European (Non-Finnish)0.00000900.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcription factor for the thyroid-specific expression of the genes exclusively expressed in the thyroid cell type, maintaining the functional differentiation of such cells.;
Disease
DISEASE: Hypothyroidism, congenital, non-goitrous, 2 (CHNG2) [MIM:218700]: A disease characterized by thyroid dysgenesis, the most frequent cause of congenital hypothyroidism, accounting for 85% of case. The thyroid gland can be completely absent (athyreosis), ectopically located and/or severely hypoplastic. Ectopic thyroid gland is the most frequent malformation, with thyroid tissue being found most often at the base of the tongue. {ECO:0000269|PubMed:11232006, ECO:0000269|PubMed:11502839, ECO:0000269|PubMed:9590296}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.570

Intolerance Scores

LoFtool
0.0270
RVIS EVS
-0.47
RVIS percentile EVS
23.43

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.787

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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