HHAT

protein-coding

hedgehog acyltransferase, the group of Membrane bound O-acyltransferase family

Gene summary

'Skinny hedgehog' (SKI1) encodes an enzyme that acts within the secretory pathway to catalyze amino-terminal palmitoylation of 'hedgehog' (see MIM 600725).[supplied by OMIM, Jul 2002]

MANE transcript

NM_018194.6

Inheritance

ClinVar variants

P:9U:101B:42

Top phenotype

Nivelon-Nivelon-Mabille syndrome

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr1:210,328,252-210,676,296

External References & Databases

Ensembl (ENSG00000054392)

Transcript & Mutation Effects

hg38 • Region Span ~348.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

chondrodysplasia-pseudohermaphroditism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010814

Submitter: PanelApp Australia

chondrodysplasia-pseudohermaphroditism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010814

Submitter: Orphanet

chondrodysplasia-pseudohermaphroditism syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010814

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Nivelon-Nivelon-Mabille syndromeAR

Manifestation: Craniofacial; Genitourinary; 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: 1342874; 24784881; 30912300

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HHAT variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 84

not providedTotal: 69

HHAT-related disorderTotal: 15

Chondrodysplasia-pseudohermaphroditism syndromeTotal: 9

Inborn genetic diseasesTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018194.6. 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	21 clinvar	6 clinvar	29
missense	2 clinvar		94 clinvar	13 clinvar	2 clinvar	111
nonsense	3 clinvar	2 clinvar				5
start loss		1 clinvar	1 clinvar			2
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	6	3	101	34	8	152

Highest pathogenic variant AF is 0.0000131392235

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 54 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018194.6	RefSeq	NP_060664.2	11	MANE Select
ENST00000261458.8	Ensembl	ENSP00000261458.3	11	MANE Select
NM_001122834.4	RefSeq	NP_001116306.1	11	Standard
NM_001170564.3	RefSeq	NP_001164035.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

HH-Ncore
Signal Transduction
Hedgehog
Hedgehog ligand biogenesis
Signaling by Hedgehog

Biological Process

smoothened signaling pathway
multicellular organism development
protein palmitoylation

Molecular Function

GTP binding
O-acyltransferase activity
palmitoyltransferase activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000545154
Coding exons: 11
Length: 348043
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 48
Defined: 125748
p: 0.000191

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0546	272	275	0.991	0.0000154	3161
Missense (PolyPhen)		102	97.336	1.0479		1140
Synonymous	0.941	105	118	0.890	0.00000730	989
Loss of Function	2.26	17	30.4	0.558	0.00000146	315

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00033	0.00033	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00014	rare
South Asian	0.00043	0.00042	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes N-terminal palmitoylation of SHH; which is required for SHH signaling. May bind GTP. {ECO:0000250, ECO:0000269|PubMed:11486055}.;

Intolerance Scores

LoFtool: 0.961
RVIS EVS: -0.02
RVIS percentile EVS: 52.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.946

Gene Damage Prediction

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