HAX1

HCLS1 associated protein X-1

Basic information

Region (hg38): 1:154272354-154275875

Links

ENSG00000143575 ∙ NCBI:10456 ∙ OMIM:605998 ∙ HGNC:16915 ∙ Uniprot:O00165 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Kostmann syndrome (Definitive), mode of inheritance: AR
• Kostmann syndrome (Strong), mode of inheritance: AR
• Kostmann syndrome (Supportive), mode of inheritance: AR
• Kostmann syndrome (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neutropenia, severe congenital, 3	AR	Allergy/Immunology/Infectious; Oncologic	Individuals manifest with findings including susceptibility to severe bacterial infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; Use of G-CSF has been reported, as well as treatment with BMT; Surveillance for malignancies may allow early detection and treatment, as there is an increased risk of manifestations such as acute myeloid leukemia and myelodysplastic syndrome	Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Neurologic; Oncologic	13326376; 17187068; 18337561; 21108402

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HAX1 gene.

• Kostmann syndrome (301 variants)
• not provided (29 variants)
• not specified (24 variants)
• Inborn genetic diseases (14 variants)
• Severe congenital neutropenia (4 variants)
• HAX1-related condition (2 variants)
• Hereditary insensitivity to pain with anhidrosis (1 variants)
• Neutropenia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HAX1 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				94		94
missense			92	3		95
nonsense	10	2	1			13
start loss						0
frameshift	13	2				15
inframe indel			9	2		11
splice donor/acceptor (+/-2bp)	1	9				10
splice region			4	20		24
non coding			7	41	6	54
Total	24	13	109	140	6

Highest pathogenic variant AF is 0.0000723

Variants in HAX1

This is a list of pathogenic ClinVar variants found in the HAX1 region.

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

Position	Type	Phenotype	Significance	ClinVar
1-154272574-A-T		Kostmann syndrome	Uncertain significance (Jan 12, 2018)
1-154272666-T-G		Kostmann syndrome	Benign (Jul 08, 2021)
1-154272666-TC-T		Severe congenital neutropenia	Likely benign (Jun 14, 2016)
1-154272670-CCG-C			Benign (Mar 03, 2015)
1-154272671-CG-T			Benign (Mar 03, 2015)
1-154272672-G-T		Kostmann syndrome	Benign (Jan 12, 2018)
1-154272719-C-T		not specified	Likely benign (Sep 11, 2019)
1-154272732-C-G		Kostmann syndrome	Likely benign (Oct 13, 2020)
1-154272732-C-T		Kostmann syndrome	Likely benign (Apr 10, 2021)
1-154272732-CTT-C		Kostmann syndrome	Pathogenic (Oct 04, 2023)
1-154272734-T-C		Kostmann syndrome	Uncertain significance (Apr 14, 2022)
1-154272735-T-C		Kostmann syndrome	Likely benign (Apr 14, 2023)
1-154272737-A-C		Kostmann syndrome	Uncertain significance (Aug 30, 2021)
1-154272738-T-A		Kostmann syndrome	Uncertain significance (Oct 28, 2022)
1-154272738-TC-T		Kostmann syndrome	Pathogenic (Apr 22, 2023)
1-154272741-C-G		Kostmann syndrome	Likely benign (Dec 30, 2023)
1-154272741-C-T		Kostmann syndrome • HAX1-related disorder	Likely benign (Dec 18, 2023)
1-154272744-C-T		Kostmann syndrome	Likely benign (Sep 05, 2021)
1-154272747-G-A		Kostmann syndrome	Likely benign (Apr 06, 2023)
1-154272750-C-T		Kostmann syndrome	Likely benign (Dec 12, 2021)
1-154272753-T-C		Kostmann syndrome	Likely benign (Sep 08, 2023)
1-154272755-T-C		Kostmann syndrome	Uncertain significance (Jul 15, 2022)
1-154272759-C-G		Kostmann syndrome	Likely benign (Jan 01, 2024)
1-154272765-T-G		Kostmann syndrome	Likely benign (Mar 31, 2023)
1-154272766-G-T		Kostmann syndrome	Pathogenic (Jun 14, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HAX1	protein_coding	protein_coding	ENST00000328703	7	3365

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.48e-8	0.303	125640	0	108	125748	0.000430

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.136	158	163	0.970	0.00000973	1855
Missense in Polyphen		34	47.996	0.70839		604
Synonymous	0.794	49	56.6	0.866	0.00000304	539
Loss of Function	0.523	12	14.1	0.850	8.47e-7	142

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000828	0.000821
Ashkenazi Jewish	0.000695	0.000695
East Asian	0.000761	0.000761
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000581	0.000580
Middle Eastern	0.000761	0.000761
South Asian	0.0000653	0.0000653
Other	0.000489	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Recruits the Arp2/3 complex to the cell cortex and regulates reorganization of the cortical actin cytoskeleton via its interaction with KCNC3 and the Arp2/3 complex (PubMed:26997484). Slows down the rate of inactivation of KCNC3 channels (PubMed:26997484). Promotes GNA13-mediated cell migration. Involved in the clathrin-mediated endocytosis pathway. May be involved in internalization of ABC transporters such as ABCB11. May inhibit CASP9 and CASP3. Promotes cell survival. May regulate intracellular calcium pools. {ECO:0000269|PubMed:15339924, ECO:0000269|PubMed:16857965, ECO:0000269|PubMed:17545607, ECO:0000269|PubMed:18319618, ECO:0000269|PubMed:18971376, ECO:0000269|PubMed:26997484, ECO:0000269|PubMed:9058808}.
• Disease: DISEASE: Neutropenia, severe congenital 3, autosomal recessive (SCN3) [MIM:610738]: A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. Some patients affected by severe congenital neutropenia type 3 have neurological manifestations such as psychomotor retardation and seizures. {ECO:0000269|PubMed:17187068, ECO:0000269|PubMed:18337561, ECO:0000269|PubMed:19796188, ECO:0000269|PubMed:20220065}. Note=The disease is caused by mutations affecting the gene represented in this entry. The clinical phenotype due to HAX1 deficiency appears to depend on the localization of the mutations and their influence on the transcript variants. Mutations affecting exclusively isoform 1 are associated with isolated congenital neutropenia, whereas mutations affecting both isoform 1 and isoform 5 are associated with additional neurologic symptoms (PubMed:18337561). {ECO:0000269|PubMed:18337561}.

Recessive Scores

• pRec: 0.205

Intolerance Scores

• loftool: 0.976
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.31

Haploinsufficiency Scores

• pHI: 0.133
• hipred: N
• hipred_score: 0.394
• ghis: 0.599

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.967

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Hax1
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system 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); 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); skeleton phenotype; immune system phenotype; cellular phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: mitochondrion organization;positive regulation of phosphatidylinositol 3-kinase signaling;regulation of actin filament polymerization;positive regulation of granulocyte differentiation;positive regulation of peptidyl-serine phosphorylation;regulation of apoptotic process;negative regulation of apoptotic process;positive regulation of transcription by RNA polymerase II;positive regulation of peptidyl-tyrosine phosphorylation;positive regulation of protein kinase B signaling;cellular response to cytokine stimulus;regulation of autophagy of mitochondrion;regulation of protein targeting to mitochondrion;positive regulation of actin cytoskeleton reorganization
• Cellular component: P-body;nuclear envelope;transcription factor complex;mitochondrion;mitochondrial outer membrane;mitochondrial intermembrane space;endoplasmic reticulum;plasma membrane;cell cortex;actin cytoskeleton;sarcoplasmic reticulum;lamellipodium;cytoplasmic vesicle;nuclear membrane
• Molecular function: protein binding;interleukin-1 binding;protein N-terminus binding