SOX5

protein-coding

SRY-box transcription factor 5, the group of SRY-box transcription factors

Gene summary

This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. The encoded protein may play a role in chondrogenesis. A pseudogene of this gene is located on chromosome 8. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006940.6

Inheritance

ClinVar variants

P:93U:179B:52

Top phenotype

Lamb-Shaffer syndrome

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr12:23,529,504-24,562,544

External References & Databases

Ensembl (ENSG00000134532)

Transcript & Mutation Effects

hg38 • Region Span ~1,033.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Lamb-Shaffer syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014778

Submitter: ClinGen

*SOX5* variants were first reported in relation to autosomal dominant Lamb-Shaffer syndrome in 2012 (Lamb et al., PMID:22290657). *SOX5* encodes a SRY-related HMG-box transcription factor involved in the regulation of embryonic development, chondrogenesis, and nervous system development. Lamb-Shaffer syndrome is characterized by developmental delay/intellectual disability, autism spectrum disorder, hypotonia, skeletal defects, dysmorphic facial features including frontal bossing, facial asymmetry, strabismus, depressed nasal bridge, bulbous nasal tip and crowded teeth. At least 10 unique heterozygous variants (large deletions, translocations, truncating and missense) have been reported in 10 probands in 5 publications (PMIDs:22290657, 29477873, 31578471, 33296143, 234938568) included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Two subjects from Lamb et al (PMID:22290657) and one from Lee et al (PMID:23498568) included in the curation were unable to be entered for scoring due the limitations of the gene curation interface. Details of these subjects are as follows: Lamb et al reported Subject 2, a 4 year old female with a 137 kb de novo intragenic *SOX5* deletion and global developmental delay (2 points) and Subject 6, a 4 year old male with a 133 kb intragenic *SOX5* deletion and global developmental delay, strabismus, and frontal bossing (1.5 points). These variants were identified via oligonucleotide-based aCGH. Lee et al reported a 32 month-old male with a 53 kb de novo *SOX5* deletion identified by chromosomal microarray and intellectual disability, speech delay and frontal bossing (2 points). Inclusion of these three individuals contributed 5.5 points to this curation. This gene-disease relationship is also supported by experimental evidence. Dy et al (PMID:18543318) generated a conditional null mouse model that demonstrated generalized chrondrodysplasia. The skeletal defects present in this model are similar to those observed in individuals with Lamb-Shaffer syndrome. Due to a lack of a neurodevelopmental phenotype in this model, the score has been downgraded. In summary, *SOX5* is definitively associated with autosomal dominant Lamb-Shaffer syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 01/27/2022 (SOP version 8).

Lamb-Shaffer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014778

Submitter: G2P

developmental and speech delay due to SOX5 deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017782

Submitter: Orphanet

Lamb-Shaffer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014778

Submitter: PanelApp Australia

Lamb-Shaffer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014778

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Lamb-Shaffer syndromeAD

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: 22290657; 23220431; 23498568; 26111154

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SOX5 variants in ClinVar

21 Conditions Cataloged

not providedTotal: 146

Lamb-Shaffer syndromeTotal: 108

Inborn genetic diseasesTotal: 85

SOX5-related disorderTotal: 31

not specifiedTotal: 20

Intellectual disabilityTotal: 5

Generalized hypotoniaTotal: 2

Epileptic encephalopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006940.6. 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			2 clinvar	26 clinvar	4 clinvar	32
missense	5 clinvar	21 clinvar	171 clinvar	21 clinvar		218
nonsense	16 clinvar	10 clinvar				26
start loss			1 clinvar			1
frameshift	17 clinvar	8 clinvar	2 clinvar			27
splice donor/acceptor (+/-2bp)	10 clinvar	6 clinvar	3 clinvar	1 clinvar		20
Total	48	45	179	48	4	324

Highest pathogenic variant AF is 0.000006573585

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 70 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006940.6	RefSeq	NP_008871.3	15	MANE Select
ENST00000451604.7	Ensembl	ENSP00000398273.2	15	MANE Select
NM_001261414.3	RefSeq	NP_001248343.1	12	Standard
NM_001261415.3	RefSeq	NP_001248344.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neural Crest Differentiation
Endochondral Ossification

Biological Process

transcription by RNA polymerase II
positive regulation of chondrocyte differentiation
cell fate commitment
negative regulation of transcription, DNA-templated
positive regulation of transcription by RNA polymerase II

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000451604
Coding exons: 15
Length: 421527
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125745
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.15	244	427	0.571	0.0000232	5018
Missense (PolyPhen)		77	214.81	0.35845		2495
Synonymous	-0.210	159	156	1.02	0.00000852	1478
Loss of Function	5.52	3	41.2	0.0728	0.00000215	458

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds specifically to the DNA sequence 5'-AACAAT-3'. Activates transcription of COL2A1 and AGC1 in vitro.;
Disease: DISEASE: Lamb-Shaffer syndrome (LAMSHF) [MIM:616803]: An autosomal dominant, neurodevelopmental disorder characterized by global developmental delay, intellectual disability, language and motor impairment, and distinct facial features. Additional variable skeletal abnormalities may also be present. {ECO:0000269|PubMed:22290657, ECO:0000269|PubMed:23220431, ECO:0000269|PubMed:23498568, ECO:0000269|PubMed:26111154}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.178

Intolerance Scores

LoFtool: 0.0509
RVIS EVS: -0.96
RVIS percentile EVS: 9.09

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.804

Gene Damage Prediction

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