HAX1

protein-coding

HCLS1 associated protein X-1

Gene summary

The protein encoded by this gene is known to associate with hematopoietic cell-specific Lyn substrate 1, a substrate of Src family tyrosine kinases. It also interacts with the product of the polycystic kidney disease 2 gene, mutations in which are associated with autosomal-dominant polycystic kidney disease, and with the F-actin-binding protein, cortactin. It was earlier thought that this gene product is mainly localized in the mitochondria, however, recent studies indicate it to be localized in the cell body. Mutations in this gene result in autosomal recessive severe congenital neutropenia, also known as Kostmann disease. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006118.4

Inheritance

ClinVar variants

P:67U:359B:194

Top phenotype

Neutropenia, severe congenital, 3

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr1:154,272,355-154,275,875

External References & Databases

Ensembl (ENSG00000143575)

Transcript & Mutation Effects

hg38 • Region Span ~3.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Kostmann syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012548

Submitter: G2P

Kostmann syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012548

Submitter: Orphanet

Kostmann syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012548

Submitter: Labcorp Genetics (formerly Invitae)

Kostmann syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012548

Submitter: PanelApp Australia

Kostmann syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012548

Submitter: Natera

Kostmann syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012548

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neutropenia, severe congenital, 3AR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Neurologic; Oncologic

Intervention: Allergy/Immunology/Infectious; Oncologic

Rationale: 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

Refs: 13326376; 17187068; 18337561; 21108402

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HAX1 variants in ClinVar

9 Conditions Cataloged

Inborn genetic diseasesTotal: 438

Kostmann syndromeTotal: 419

not providedTotal: 54

not specifiedTotal: 39

HAX1-related disorderTotal: 12

HAX1-related disordersTotal: 6

Severe congenital neutropeniaTotal: 3

Decreased total neutrophil countTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006118.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	178 clinvar		181
missense			353 clinvar	16 clinvar		369
nonsense	9 clinvar	8 clinvar				17
start loss						0
frameshift	23 clinvar	11 clinvar	1 clinvar			35
splice donor/acceptor (+/-2bp)	2 clinvar	14 clinvar	2 clinvar			18
Total	34	33	359	194	0	620

Highest pathogenic variant AF is 0.00048160122

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006118.4	RefSeq	NP_006109.2	7	MANE Select
ENST00000328703.12	Ensembl	ENSP00000329002.7	7	MANE Select
NM_001018837.2	RefSeq	NP_001018238.1	7	Standard
ENST00000435087.2	Ensembl	ENSP00000394920.2	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

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

Molecular Function

protein binding
interleukin-1 binding
protein N-terminus binding

Cellular Component

P-body
nuclear envelope
transcription factor complex
mitochondrion
mitochondrial outer membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000328703
Coding exons: 7
Length: 3365
Individuals with no LoFs: 125640
Homozygous LoFs: 0
Heterozygous LoFs: 108
Defined: 125748
p: 0.000430

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.136	158	163	0.970	0.00000973	1855
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00014	0.000087	rare
Ashkenazi Jewish	0.00069	0.00069	rare
East Asian	0.00076	0.00076	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00058	0.00058	rare
South Asian	0.000065	0.000065	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

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

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.967

Gene Damage Prediction

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