SHOX

short stature homeobox, the group of Pseudoautosomal region 1|PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): X:624343-659411

Links

ENSG00000185960 ∙ NCBI:6473 ∙ OMIM:312865, 400020 ∙ HGNC:10853 ∙ Uniprot:O15266 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Langer mesomelic dysplasia (Definitive), mode of inheritance: XLR
• Leri-Weill dyschondrosteosis (Definitive), mode of inheritance: XLD
• Leri-Weill dyschondrosteosis (Supportive), mode of inheritance: AD
• Langer mesomelic dysplasia (Supportive), mode of inheritance: AR
• SHOX-related short stature (Supportive), mode of inheritance: AD
• Leri-Weill dyschondrosteosis (Definitive), mode of inheritance: XL
• Langer mesomelic dysplasia (Moderate), mode of inheritance: Unknown
• Langer mesomelic dysplasia (Strong), mode of inheritance: XL
• Leri-Weill dyschondrosteosis (Strong), mode of inheritance: XL
• Langer mesomelic dysplasia (Definitive), mode of inheritance: XL
• Leri-Weill dyschondrosteosis (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Langer mesomelic dysplasia; Leri-Weill dyschondrosteosis; Short stature, idiopathic familial	XL/PAR	General	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	Musculoskeletal	14344358; 5410085; 6059604; 7365762; 9140395; 9590292; 9590293; 11030412; 11186941; 10713888; 11403039; 11739418; 11932348; 14557470; 12784295; 15173249; 15173321; 15214013; 16227037; 17935511; 17047016; 17200153; 19578035; 19636220; 20301394; 20412871; 20538086; 20683993; 21712857; 21912078; 22020182; 22071895; 22461651; 22518848; 22572840
GH treatment can be effective in idiopathic short stature; Deletion of regulatory elements can also produce manifestations

ClinVar

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

• not provided (184 variants)
• not specified (106 variants)
• Leri-Weill dyschondrosteosis (36 variants)
• SHOX-related short stature (24 variants)
• Connective tissue disorder (10 variants)
• Langer mesomelic dysplasia syndrome (8 variants)
• Leri-Weill dyschondrosteosis;SHOX-related short stature;Langer mesomelic dysplasia syndrome (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SHOX 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			8	14	6	28
missense	12	8	114	2		136
nonsense	12	4				16
start loss						0
frameshift	16	4				20
inframe indel	2		6			8
splice donor/acceptor (+/-2bp)		2	2			4
splice region			8	2	4	14
non coding		2	20	8	20	50
Total	42	20	150	24	26

Highest pathogenic variant AF is 0.0000131

Variants in SHOX

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

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

Position	Type	Phenotype	Significance	ClinVar
X-624386-C-G		SHOX-related short stature	Likely benign (-)
X-624386-CT-C		SHOX-related disorder	Benign (Feb 16, 2021)
X-624386-C-CT		SHOX-related disorder	Benign (Feb 16, 2021)
X-624386-C-CTT		SHOX-related disorder	Likely benign (Feb 16, 2021)
X-624387-T-TTTG		SHOX-related disorder	Likely benign (May 04, 2021)
X-624389-T-G			Likely benign (Dec 01, 2022)
X-624388-T-TTTG		SHOX-related short stature	Pathogenic (-)
X-624523-C-A		SHOX-related short stature • not specified • SHOX-related disorder	Benign (May 19, 2022)
X-624528-G-C		SHOX-related short stature • not specified • Connective tissue disorder	Benign (Apr 15, 2022)
X-630307-A-G			Benign (Jun 19, 2021)
X-630370-G-A		not specified	Benign (May 10, 2018)
X-630382-C-G			Uncertain significance (Nov 16, 2017)
X-630421-C-T			Uncertain significance (Dec 21, 2017)
X-630442-TTGTCTCTC-T		Connective tissue disorder	Likely benign (May 01, 2020)
X-630463-C-A		not specified • Leri-Weill dyschondrosteosis	Conflicting classifications of pathogenicity (May 04, 2022)
X-630526-G-A		SHOX-related short stature	Uncertain significance (Mar 03, 2016)
X-630833-C-A		SHOX-related short stature • not specified	Uncertain significance (Dec 19, 2023)
X-630843-C-T		not specified • Connective tissue disorder • SHOX-related disorder	Conflicting classifications of pathogenicity (Oct 15, 2020)
X-630879-G-A		SHOX-related short stature • Leri-Weill dyschondrosteosis	Pathogenic/Likely pathogenic (May 04, 2022)
X-630879-G-C		not specified	Benign (Oct 28, 2016)
X-630887-CG-C		not specified	Likely benign (Dec 01, 2020)
X-630934-G-A			Uncertain significance (Jan 21, 2020)
X-630935-A-G		Langer mesomelic dysplasia syndrome	Uncertain significance (Jul 29, 2018)
X-630937-C-T			Pathogenic (Feb 01, 2022)
X-630946-A-T		SHOX-related short stature	Likely pathogenic (Dec 01, 2008)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SHOX	protein_coding	protein_coding	ENST00000381578	5	35068

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.666	0.333	125580	0	6	125586	0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.538	168	149	1.12	0.00000750	1887
Missense in Polyphen		44	56.999	0.77195		736
Synonymous	-3.41	97	62.6	1.55	0.00000334	577
Loss of Function	2.71	2	12.2	0.164	5.85e-7	135

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000552	0.0000529
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Controls fundamental aspects of growth and development.
• Disease: DISEASE: Leri-Weill dyschondrosteosis (LWD) [MIM:127300]: Dominantly inherited skeletal dysplasia characterized by moderate short stature predominantly because of short mesomelic limb segments. It is often associated with the Madelung deformity of the wrist, comprising bowing of the radius and dorsal dislocation of the distal ulna. {ECO:0000269|PubMed:11030412, ECO:0000269|PubMed:11403039}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Langer mesomelic dysplasia (LMD) [MIM:249700]: Autosomal recessive rare skeletal dysplasia characterized by severe short stature owing to shortening and maldevelopment of the mesomelic and rhizomelic segments of the limbs. Associated malformations are rarely reported and intellect is normal in all affected subjects reported to date. {ECO:0000269|PubMed:11889214}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short stature, idiopathic, X-linked (ISS) [MIM:300582]: A condition defined by a standing height more than 2 standard deviations below the mean (or below the 2.5 percentile) for sex and chronological age, compared with a well-nourished, genetically relevant population, in the absence of specific causative disorders. {ECO:0000269|PubMed:9140395}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Haploinsufficiency Scores

• pHI: 0.101
• hipred: Y
• hipred_score: 0.725
• ghis: 0.481

Essentials

• essential_gene_CRISPR: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.731

Gene Damage Prediction

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

Zebrafish Information Network

• Gene name: shox
• Affected structure: cranial vault
• Phenotype tag: abnormal
• Phenotype quality: decreased process quality

Gene ontology

• Biological process: skeletal system development;transcription by RNA polymerase II;positive regulation of transcription by RNA polymerase II
• Cellular component: nucleoplasm;intracellular membrane-bounded organelle
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA-binding transcription factor activity;protein binding;sequence-specific DNA binding