ALX3

protein-coding

ALX homeobox 3, the group of PRD class homeoboxes and pseudogenes

Gene summary

This gene encodes a nuclear protein with a homeobox DNA-binding domain that functions as a transcriptional regulator involved in cell-type differentiation and development. Preferential methylation of this gene's promoter is associated with advanced-stage neuroblastoma tumors. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_006492.3

Inheritance

ClinVar variants

P:10U:67B:18

Top phenotype

Frontonasal dysplasia 1

gnomAD constraint

pLI —, LoF o/e 0.45

Max pathogenic AF

—

Genomic locus

chr1:110,059,870-110,070,672

External References & Databases

Ensembl (ENSG00000156150)

Transcript & Mutation Effects

hg38 • Region Span ~10.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

frontorhinySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007636

Submitter: Labcorp Genetics (formerly Invitae)

frontorhinyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007636

Submitter: G2P

frontorhinySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007636

Submitter: Orphanet

frontorhinySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0007636

Submitter: PanelApp Australia

frontorhinyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0007636

Submitter: ClinGen

ALX3 has been repeatedly described in association with autosomal recessive Frontonasal dysplasia 1 also known as Frontorhiny. Frontonasal dysplasia 1 is characterized by having a distinctive facial appearance with hypertelorism, broad nasal bridge, short nasal ridge, splayed nasal bones with bifid nasal tip, broad columella that attaches to the lip above the alae, widely separated slit-like nares, long philtrum with prominent bilateral swellings, and midline notch in the upper lip and alveolus. At least 1 missense, 2 nonsense, 1 splice acceptor, 1 deletion mutations have been reported in at least 5 probands from 4 publications (PMIDs: 19409524, 22106187, 29215096, 34098755) This gene disease association is also supported by experimental evidence including expression data and an animal model (PMID:20534379) . In summary ALX3 is definitively associated with autosomal recessive Frontonasal dysplasia 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations Gene Curation Expert Panel on 10/13/2022. (SOP Version 9)

Clinical Genomic Database (CGD)

Frontonasal dysplasia 1AR

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: 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

Refs: 17963218; 19409524; 22106187

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALX3 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 60

not providedTotal: 30

FrontorhinyTotal: 11

not specifiedTotal: 8

ALX3-related disorderTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006492.3. 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				13 clinvar	2 clinvar	15
missense	3 clinvar		66 clinvar	3 clinvar		72
nonsense	4 clinvar					4
start loss						0
frameshift	1 clinvar	1 clinvar				2
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	9	1	67	16	2	95

Highest pathogenic variant AF is 0.000003717403

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006492.3	RefSeq	NP_006483.2	4	MANE Select
ENST00000647563.2	Ensembl	ENSP00000497310.1	4	MANE Select
ENST00000649954.1	Ensembl	ENSP00000497035.1	3	Standard
ENST00000649954.2	Ensembl	ENSP00000497035.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of transcription by RNA polymerase II
pattern specification process
embryonic forelimb morphogenesis
embryonic hindlimb morphogenesis
regulation of apoptotic process

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000369792
Coding exons: 4
Length: 10707
Individuals with no LoFs: 125740
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125747
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.446	151	167	0.903	0.0000103	2178
Missense (PolyPhen)		54	78.396	0.68881		805
Synonymous	0.475	63	68.0	0.927	0.00000385	752
Loss of Function	1.51	4	8.87	0.451	4.64e-7	122

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional regulator with a possible role in patterning of mesoderm during development. {ECO:0000250}.;
Disease: DISEASE: Frontonasal dysplasia 1 (FND1) [MIM:136760]: The term frontonasal dysplasia describes an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism; broadening of the nasal root; median facial cleft affecting the nose and/or upper lip and palate; unilateral or bilateral clefting of the alae nasi; lack of formation of the nasal tip; anterior cranium bifidum occultum; a V-shaped or widow's peak frontal hairline. {ECO:0000269|PubMed:19409524}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0999

Intolerance Scores

LoFtool: 0.150
RVIS EVS: -0.25
RVIS percentile EVS: 35.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.467

Gene Damage Prediction

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