CERS3

protein-coding

ceramide synthase 3, the group of CERS class homeoboxes

Gene summary

This gene is a member of the ceramide synthase family of genes. The ceramide synthase enzymes regulate sphingolipid synthesis by catalyzing the formation of ceramides from sphingoid base and acyl-coA substrates. This family member is involved in the synthesis of ceramides with ultra-long-chain acyl moieties (ULC-Cers), important to the epidermis in its role in creating a protective barrier from the environment. The protein encoded by this gene has also been implicated in modification of the lipid structures required for spermatogenesis. Mutations in this gene have been associated with male fertility defects, and epidermal defects, including ichthyosis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

Previous symbols:

LASS3

MANE transcript

NM_001378789.1

Inheritance

ClinVar variants

P:23U:47B:36

Top phenotype

Ichthyosis, congenital, autosomal recessive 9

gnomAD constraint

pLI —, LoF o/e 0.35

Max pathogenic AF

—

Genomic locus

chr15:100,400,395-100,544,995

External References & Databases

Ensembl (ENSG00000154227)

Transcript & Mutation Effects

hg38 • Region Span ~144.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive congenital ichthyosis 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014010

Submitter: Genomics England PanelApp

autosomal recessive congenital ichthyosis 9LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014010

Submitter: G2P

congenital non-bullous ichthyosiform erythrodermaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019306

Submitter: Orphanet

autosomal recessive congenital ichthyosis 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014010

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Ichthyosis, congenital, autosomal recessive 9AR

Manifestation: Dermatologic

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: 23549421; 23754960

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CERS3 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 54

Inborn genetic diseasesTotal: 48

Autosomal recessive congenital ichthyosis 9Total: 14

CERS3-related disorderTotal: 8

not specifiedTotal: 6

Ichthyosis and erythrokeratodermaTotal: 4

Lamellar ichthyosisTotal: 2

Abnormality of the skinTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378789.1. 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				15 clinvar	4 clinvar	19
missense	4 clinvar	3 clinvar	44 clinvar	14 clinvar	3 clinvar	68
nonsense	2 clinvar	2 clinvar	1 clinvar			5
start loss						0
frameshift	2 clinvar	4 clinvar				6
splice donor/acceptor (+/-2bp)		6 clinvar	2 clinvar			8
Total	8	15	47	29	7	106

Highest pathogenic variant AF is 0.000024849938

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 17 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378789.1	RefSeq	NP_001365718.1	10	MANE Select
ENST00000679737.1	Ensembl	ENSP00000506641.1	10	MANE Select
NM_001290341.2	RefSeq	NP_001277270.1	11	Standard
NM_001290342.2	RefSeq	NP_001277271.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Sphingolipid signaling pathway - Homo sapiens (human)
Sphingolipid metabolism - Homo sapiens (human)
Sphingolipid Metabolism
Metabolism of lipids
Metabolism

Biological Process

regulation of transcription by RNA polymerase II
sphingolipid biosynthetic process
keratinocyte differentiation
ceramide biosynthetic process

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
sphingosine N-acyltransferase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane
nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000284382
Coding exons: 10
Length: 144601
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125745
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.613	183	208	0.880	0.0000110	2537
Missense (PolyPhen)		59	75.724	0.77915		952
Synonymous	-0.400	78	73.6	1.06	0.00000412	658
Loss of Function	2.90	8	23.0	0.347	0.00000105	269

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has (dihydro)ceramide synthesis activity with relatively broad substrate specificity, but a preference for C18:0 and other middle- to long-chain fatty acyl-CoAs (By similarity). It is crucial for the synthesis of very long-chain ceramides in the epidermis, to maintain epidermal lipid homeostasis and terminal differentiation. {ECO:0000250, ECO:0000269|PubMed:23754960}.;

Recessive Scores

pRec: 0.0785

Intolerance Scores

RVIS EVS: 0.75
RVIS percentile EVS: 86.71

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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