NKX3-2

NK3 homeobox 2, the group of NKL subclass homeoboxes and pseudogenes

Basic information

Region (hg38): 4:13540830-13544508

Previous symbols: [ "BAPX1" ]

Links

ENSG00000109705 ∙ NCBI:579 ∙ OMIM:602183 ∙ HGNC:951 ∙ Uniprot:P78367 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• spondylo-megaepiphyseal-metaphyseal dysplasia (Moderate), mode of inheritance: AR
• spondylo-megaepiphyseal-metaphyseal dysplasia (Strong), mode of inheritance: AR
• spondylo-megaepiphyseal-metaphyseal dysplasia (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spondylo-megaepiphyseal-metaphyseal dysplasia	AR	General	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	Musculoskeletal	3925497; 13680008; 20004766

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NKX3-2 gene.

• not provided (3 variants)
• Spondylo-megaepiphyseal-metaphyseal dysplasia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NKX3-2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				42	6	48
missense			76	9	1	86
nonsense	1					1
start loss						0
frameshift	2	1				3
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region			2	3		5
non coding			1	4	3	8
Total	3	1	77	55	10

Highest pathogenic variant AF is 0.00000657

Variants in NKX3-2

This is a list of pathogenic ClinVar variants found in the NKX3-2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-13541817-A-G			Benign (Jul 03, 2019)
4-13542008-G-A			Likely benign (Nov 06, 2023)
4-13542026-G-A			Likely benign (Sep 29, 2022)
4-13542053-C-G		not specified	Benign (Jan 06, 2025)
4-13542066-G-T			Uncertain significance (Jul 29, 2022)
4-13542076-G-C			Likely benign (Dec 03, 2024)
4-13542089-G-A		NKX3-2-related disorder	Likely benign (Mar 14, 2019)
4-13542089-G-T			Likely benign (Dec 10, 2023)
4-13542097-G-C		Inborn genetic diseases	Uncertain significance (Apr 17, 2024)
4-13542108-C-T		Inborn genetic diseases	Uncertain significance (Dec 09, 2023)
4-13542112-G-T		Inborn genetic diseases	Uncertain significance (Jun 17, 2024)
4-13542113-C-A			Likely benign (Feb 14, 2020)
4-13542113-C-T			Likely benign (Nov 01, 2024)
4-13542122-T-C			Conflicting classifications of pathogenicity (Nov 18, 2024)
4-13542128-G-A			Likely benign (Jan 09, 2023)
4-13542134-G-C			Likely benign (May 06, 2024)
4-13542135-C-A		Inborn genetic diseases	Uncertain significance (May 17, 2023)
4-13542152-G-A			Likely benign (Sep 01, 2021)
4-13542166-C-A		Inborn genetic diseases	Uncertain significance (Nov 11, 2024)
4-13542173-C-A			Likely benign (Oct 17, 2024)
4-13542206-G-A			Likely benign (Oct 30, 2024)
4-13542275-G-A			Likely benign (Jul 16, 2023)
4-13542278-C-T			Likely benign (Mar 23, 2022)
4-13542284-T-A			Likely benign (Apr 03, 2024)
4-13542295-G-A		NKX3-2-related disorder	Uncertain significance (Jul 05, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NKX3-2	protein_coding	protein_coding	ENST00000382438	2	4221

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.638	0.356	123278	0	2	123280	0.00000811

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.596	193	171	1.13	0.00000790	2017
Missense in Polyphen		54	58.171	0.92829		710
Synonymous	-1.71	98	78.7	1.25	0.00000400	724
Loss of Function	2.20	1	7.52	0.133	3.21e-7	101

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.000144	0.0000474
European (Non-Finnish)	0.00000973	0.00000904
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Transcriptional repressor that acts as a negative regulator of chondrocyte maturation. PLays a role in distal stomach development; required for proper antral-pyloric morphogenesis and development of antral-type epithelium. In concert with GSC, defines the structural components of the middle ear; required for tympanic ring and gonium development and in the regulation of the width of the malleus (By similarity). {ECO:0000250}.
• Pathway: Endochondral Ossification;Transcriptional regulation by RUNX2;Gene expression (Transcription);Generic Transcription Pathway;RNA Polymerase II Transcription;Regulation of RUNX2 expression and activity (Consensus)

Recessive Scores

• pRec: 0.141

Haploinsufficiency Scores

• pHI: 0.285
• hipred: N
• hipred_score: 0.490

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.925

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nkx3-2
• Phenotype: embryo phenotype; respiratory system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; limbs/digits/tail phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; immune system phenotype; skeleton phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; muscle phenotype; craniofacial phenotype; cellular phenotype

Zebrafish Information Network

• Gene name: nkx3.2
• Affected structure: pharyngeal arch 1
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;skeletal system development;transcription by RNA polymerase II;determination of left/right symmetry;cell differentiation;pancreas development;negative regulation of chondrocyte differentiation;middle ear morphogenesis;negative regulation of apoptotic process;positive regulation of transcription by RNA polymerase II;spleen development;animal organ formation;skeletal system morphogenesis;embryonic skeletal system development;intestinal epithelial cell development
• Cellular component: nucleus
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription repressor activity, RNA polymerase II-specific;DNA-binding transcription factor activity;sequence-specific DNA binding