SALL4

protein-coding

spalt like transcription factor 4, the group of Zinc fingers C2H2-type

Gene summary

This gene encodes a zinc finger transcription factor thought to play a role in the development of abducens motor neurons. Defects in this gene are a cause of Duane-radial ray syndrome (DRRS). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

MANE transcript

NM_020436.5

Inheritance

ClinVar variants

P:60U:333B:216

Top phenotype

Duane-radial ray/Okohiro syndrome; IVIC syndrome

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr20:51,782,331-51,802,521

External References & Databases

Ensembl (ENSG00000101115)

Transcript & Mutation Effects

hg38 • Region Span ~20.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Duane retraction syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007473

Submitter: Orphanet

IVIC syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007836

Submitter: Orphanet

Duane-radial ray syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011812

Submitter: Labcorp Genetics (formerly Invitae)

Duane-radial ray syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011812

Submitter: G2P

Duane-radial ray syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011812

Submitter: PanelApp Australia

Duane-radial ray syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011812

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Duane-radial ray/Okohiro syndrome; IVIC syndromeAD

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Ophthalmologic; Renal

Intervention: Audiologic/Otolaryngologic; Cardiovascular; Renal

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Individuals have been described with vesicoureteral reflux, and surveillance and management may be helpful to preserve renal function; The conditions can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 843249; 7395922; 12395297; 11826030; 12393809; 12789647; 12843316; 12868480; 15342710; 16086360; 16402211; 16411190; 17256792; 20301547

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SALL4 variants in ClinVar

9 Conditions Cataloged

Duane-radial ray syndromeTotal: 402

not providedTotal: 172

Oculootoradial syndromeTotal: 160

not specifiedTotal: 144

Inborn genetic diseasesTotal: 128

SALL4-Related DisordersTotal: 65

Congenital heart diseaseTotal: 1

Congenital anomaly of kidney and urinary tractTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020436.5. 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			9 clinvar	152 clinvar	4 clinvar	165
missense	1 clinvar		316 clinvar	57 clinvar	3 clinvar	377
nonsense	13 clinvar	3 clinvar	1 clinvar			17
start loss						0
frameshift	29 clinvar	12 clinvar	6 clinvar			47
splice donor/acceptor (+/-2bp)		2 clinvar	1 clinvar			3
Total	43	17	333	209	7	609

Highest pathogenic variant AF is 6.8404694e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020436.5	RefSeq	NP_065169.1	4	MANE Select
ENST00000217086.9	Ensembl	ENSP00000217086.4	4	MANE Select
NM_001318031.2	RefSeq	NP_001304960.1	4	Standard
ENST00000371539.7	Ensembl	ENSP00000360594.3	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transcriptional regulation of pluripotent stem cells
Vitamin D Receptor Pathway
Wnt-beta-catenin Signaling Pathway in Leukemia
Developmental Biology
Signal Transduction

Biological Process

negative regulation of transcription by RNA polymerase II
inner cell mass cell proliferation
neural tube closure
ventricular septum development
regulation of transcription, DNA-templated

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
transcription factor binding
metal ion binding

Cellular Component

heterochromatin
nucleus
nucleoplasm
cytoplasm
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000217086
Coding exons: 4
Length: 18479
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125748
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.07	539	614	0.878	0.0000400	6896
Missense (PolyPhen)		151	219.69	0.68733		2561
Synonymous	-2.39	320	270	1.18	0.0000205	2202
Loss of Function	5.04	0	29.5	0.00	0.00000195	340

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00014	0.00011	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor with a key role in the maintenance and self-renewal of embryonic and hematopoietic stem cells. {ECO:0000269|PubMed:23012367}.;
Disease: DISEASE: Duane-radial ray syndrome (DRRS) [MIM:607323]: Disorder characterized by the association of forearm malformations with Duane retraction syndrome. {ECO:0000269|PubMed:12393809, ECO:0000269|PubMed:12395297, ECO:0000269|PubMed:16402211}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Oculootoradial syndrome (OORS) [MIM:147750]: Autosomal dominant condition characterized by upper limbs anomalies (radial ray defects, carpal bones fusion), extraocular motor disturbances, congenital bilateral non-progressive mixed hearing loss. Other less consistent malformations include heart involvement, mild thrombocytopenia and leukocytosis (before age 50), shoulder girdle hypoplasia, imperforate anus, kidney malrotation or rectovaginal fistula. The IVIC syndrome is an allelic disorder of Duane-radial ray syndrome (DRRS) with a similar phenotype. {ECO:0000269|PubMed:17256792}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.156

Intolerance Scores

LoFtool: 0.0991
RVIS EVS: -1.47
RVIS percentile EVS: 3.73

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.811

Gene Damage Prediction

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