DHH

desert hedgehog signaling molecule, the group of Hedgehog signaling molecule family

Basic information

Region (hg38): 12:49086656-49094801

Links

ENSG00000139549 ∙ NCBI:50846 ∙ OMIM:605423 ∙ HGNC:2865 ∙ Uniprot:O43323 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 46,XY complete gonadal dysgenesis (Supportive), mode of inheritance: AD
• 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome (Supportive), mode of inheritance: AR
• 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
46,XY partial gonadal dysgenesis, with minifascicular neuropathy; 46,XY sex reversal 7; 46XY gonadal dysgenesis with minifascicular neuropathy	AD/AR	Endocrine; Genitourinary; Oncologic	Individuals may be at risk for oncologic processes related to gonadal tumors, and diagnosis and treatment (eg, with surgical removal) may be beneficial	Endocrine; Genitourinary; Neurologic; Oncologic	11017805; 15356051; 16390857; 21816240; 25927242; 28589169
Heterozygous variants have been reported associated with mosaic 45,X/46,XY karyotypes

ClinVar

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

• 46,XY sex reversal 7 (3 variants)
• 46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DHH 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			4	8	2	14
missense	2	1	35	1	1	40
nonsense	1					1
start loss						0
frameshift	1	1				2
inframe indel			2			2
splice donor/acceptor (+/-2bp)		1				1
splice region			1	1		2
non coding			10	12	11	33
Total	4	3	51	21	14

Variants in DHH

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

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

Position	Type	Phenotype	Significance	ClinVar
12-49089432-G-A		46,XY sex reversal 7	Uncertain significance (Jan 13, 2018)
12-49089458-C-A		46,XY sex reversal 7	Uncertain significance (Jan 13, 2018)
12-49089640-C-T		46,XY sex reversal 7	Likely benign (Sep 04, 2018)
12-49089700-C-A		46,XY sex reversal 7	Uncertain significance (Jan 12, 2018)
12-49089705-C-A		46,XY sex reversal 7	Uncertain significance (Jan 15, 2018)
12-49089749-C-G		46,XY sex reversal 7	Uncertain significance (Jan 12, 2018)
12-49089772-C-A		46,XY sex reversal 7	Benign (Dec 02, 2018)
12-49089794-C-A		46,XY sex reversal 7	Uncertain significance (Jan 12, 2018)
12-49089868-T-C		46,XY sex reversal 7	Likely benign (Sep 01, 2022)
12-49089916-A-T		46,XY sex reversal 7	Conflicting classifications of pathogenicity (Oct 03, 2023)
12-49089920-G-T			Uncertain significance (Nov 18, 2019)
12-49089921-G-T		Inborn genetic diseases	Uncertain significance (Aug 15, 2023)
12-49089946-C-G		DHH-related disorder	Likely benign (Apr 11, 2019)
12-49089963-GC-G		46,XY sex reversal 7	Pathogenic (Sep 01, 2004)
12-49090023-A-G		46,XY sex reversal 7	Likely pathogenic (Sep 08, 2016)
12-49090038-CG-C		46,XY sex reversal 7	Pathogenic (-)
12-49090046-A-G		46,XY sex reversal 7	Pathogenic (May 04, 2022)
12-49090070-G-T		46,XY sex reversal 7	Uncertain significance (Sep 18, 2019)
12-49090097-C-G		46,XY sex reversal 7	Uncertain significance (Feb 05, 2024)
12-49090105-A-ACGGGCCACG			Uncertain significance (Apr 19, 2022)
12-49090115-C-T		Inborn genetic diseases	Uncertain significance (May 27, 2022)
12-49090124-C-A		46,XY sex reversal 7	Uncertain significance (Apr 06, 2020)
12-49090137-C-T		Disorder of sexual differentiation	Uncertain significance (Aug 15, 2021)
12-49090190-G-T		46,XY sex reversal 7	Uncertain significance (Oct 03, 2017)
12-49090218-C-G			Uncertain significance (Apr 17, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DHH	protein_coding	protein_coding	ENST00000266991	3	5399

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.224	0.768	125681	0	11	125692	0.0000438

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.64	166	237	0.700	0.0000126	2462
Missense in Polyphen		65	110.5	0.58826		1164
Synonymous	0.661	101	110	0.920	0.00000610	907
Loss of Function	2.32	3	11.5	0.261	5.67e-7	119

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000265	0.000240
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000382	0.0000352
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Intercellular signal essential for a variety of patterning events during development. May function as a spermatocyte survival factor in the testes. Essential for testes development.
• Disease: DISEASE: Partial gonadal dysgenesis with minifascicular neuropathy 46,XY (PGD) [MIM:607080]: Characterized by the presence of a testis on one side and a streak or an absent gonad at the other, persistence of Muellerian duct structures, and a variable degree of genital ambiguity. {ECO:0000269|PubMed:11017805}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: 46,XY sex reversal 7 (SRXY7) [MIM:233420]: A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. SRXY7 patients have no functional gonads. {ECO:0000269|PubMed:15356051}. Note=The disease may be caused by mutations affecting the gene represented in this entry.
• Pathway: Hedgehog signaling pathway - Homo sapiens (human);HH-Core;Hedgehog Signaling Pathway;Hedgehog Signaling Pathway;Signaling by GPCR;Signal Transduction;Hedgehog;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Hedgehog;Release of Hh-Np from the secreting cell;Hedgehog ligand biogenesis;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;Ligand-receptor interactions;GPCR signaling-G alpha s PKA and ERK;Hedgehog ,on, state;Signaling by Hedgehog;GPCR signaling-G alpha i;Signaling events mediated by the Hedgehog family (Consensus)

Recessive Scores

• pRec: 0.392

Haploinsufficiency Scores

• pHI: 0.610
• hipred: Y
• hipred_score: 0.538
• ghis: 0.530

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.662

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Dhh
• Phenotype: reproductive system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); digestive/alimentary phenotype; endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: proteolysis;cell-cell signaling;multicellular organism development
• Cellular component: extracellular space;plasma membrane
• Molecular function: calcium ion binding;protein binding;peptidase activity;zinc ion binding