PSAT1

protein-coding

phosphoserine aminotransferase 1

Gene summary

This gene encodes a member of the class-V pyridoxal-phosphate-dependent aminotransferase family. The encoded protein is a phosphoserine aminotransferase and decreased expression may be associated with schizophrenia. Mutations in this gene are also associated with phosphoserine aminotransferase deficiency. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene have been defined on chromosomes 1, 3, and 8. [provided by RefSeq, Jul 2013]

MANE transcript

NM_058179.4

Inheritance

AR, AD

ClinVar variants

P:40U:265B:99

Top phenotype

Phosphoserine aminotransferase deficiency

gnomAD constraint

pLI —, LoF o/e 0.81

Max pathogenic AF

—

Genomic locus

chr9:78,297,125-78,330,093

External References & Databases

Ensembl (ENSG00000135069)

Transcript & Mutation Effects

hg38 • Region Span ~33.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

PSAT deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012596

Submitter: Labcorp Genetics (formerly Invitae)

Neu-Laxova syndrome 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014466

Submitter: Ambry Genetics

PSAT deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012596

Submitter: Orphanet

Neu-Laxova syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014466

Submitter: G2P

neurometabolic disorder due to serine deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018162

Submitter: ClinGen

PSAT1 was first reported in relation to autosomal recessive neurometabolic disorder due to serine deficiency in 2007 (Hart CE, et al., PMID: 17436247; reported as phosphoserine aminotransferase deficiency). At least 14 unique variants (missense and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 12 probands in 8 publications (PMIDs: 26610677, 26960553, 25152457, 17436247, 29269105, 28600779, 31903955, 32579715). Variants in this gene segregated with disease in 3 additional family member. This gene-disease association is supported by the biochemical function of PSAT1 as a phosphoserine aminotransferase (PMID: 12633500), its tissue enhanced expression in the brain (PMID: 12633500), and a knockout mouse model (PMID: 27626380). Of note, this gene has been implicated in two neurometabolic disorders due to serine deficiency, phosphoserine aminotransferase deficiency and Neu-Laxova syndrome. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no reported difference in molecular mechanisms or inheritance pattern and current assertions in the field suggest one broad phenotypic spectrum associated with serine biosynthesis defects encompassing both disorders (PMIDs: 28653176, 27161889, 26960553, 25152457). Therefore, all of the disease entities have been lumped into one disease entity, neurometabolic disorder due to serine deficiency. In summary, PSAT1 is definitively associated with autosomal recessive neurometabolic disorder due to serine deficiency.

neurometabolic disorder due to serine deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018162

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Phosphoserine aminotransferase deficiencyAR

Manifestation: Biochemical; Craniofacial; Musculoskeletal; Neurologic

Intervention: Biochemical

Rationale: Medical treatment (eg, with serine and glycine) can lead to improved outcomes, and early initiation of treatment may be beneficial

Refs: 17436247; 25152457; 29269105

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PSAT1 variants in ClinVar

9 Conditions Cataloged

Neu-Laxova syndrome 2Total: 308

not providedTotal: 238

PSAT deficiencyTotal: 44

PSAT1-related disorderTotal: 21

not specifiedTotal: 18

Inborn genetic diseasesTotal: 5

MicrocephalyTotal: 2

High myopiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_058179.4. 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				92 clinvar	2 clinvar	94
missense	3 clinvar	7 clinvar	262 clinvar	5 clinvar		277
nonsense	8 clinvar	5 clinvar				13
start loss						0
frameshift	9 clinvar	1 clinvar	2 clinvar			12
splice donor/acceptor (+/-2bp)		7 clinvar	1 clinvar			8
Total	20	20	265	97	2	404

Highest pathogenic variant AF is 0.0002726089

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_058179.4	RefSeq	NP_478059.1	9	MANE Select
ENST00000376588.4	Ensembl	ENSP00000365773.3	9	MANE Select
NM_021154.5	RefSeq	NP_066977.1	8	Standard
ENST00000347159.6	Ensembl	ENSP00000317606.2	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycine, serine and threonine metabolism - Homo sapiens (human)
Vitamin B6 metabolism - Homo sapiens (human)
3-Phosphoglycerate dehydrogenase deficiency
Non Ketotic Hyperglycinemia
Glycine and Serine Metabolism

Biological Process

L-serine biosynthetic process
pyridoxine biosynthetic process

Molecular Function

O-phospho-L-serine:2-oxoglutarate aminotransferase activity

Cellular Component

cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376588
Coding exons: 9
Length: 32951
Individuals with no LoFs: 125717
Homozygous LoFs: 0
Heterozygous LoFs: 31
Defined: 125748
p: 0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.413	185	202	0.918	0.0000110	2425
Missense (PolyPhen)		54	67.279	0.80262		835
Synonymous	0.501	73	78.7	0.928	0.00000477	715
Loss of Function	0.713	14	17.2	0.815	8.21e-7	226

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000070	0.000062	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.000098	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the reversible conversion of 3- phosphohydroxypyruvate to phosphoserine and of 3-hydroxy-2-oxo-4- phosphonooxybutanoate to phosphohydroxythreonine. {ECO:0000250|UniProtKB:P10658}.;
Disease: DISEASE: Neu-Laxova syndrome 2 (NLS2) [MIM:616038]: A form of Neu- Laxova syndrome, a lethal, autosomal recessive multiple malformation syndrome characterized by ichthyosis, marked intrauterine growth restriction, microcephaly, short neck, limb deformities, hypoplastic lungs, edema, and central nervous system anomalies. These include lissencephaly, cerebellar hypoplasia and/or abnormal/agenesis of the corpus callosum. Abnormal facial features include severe proptosis with ectropion, hypertelorism, micrognathia, flattened nose, and malformed ears. {ECO:0000269|PubMed:25152457}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.484

Intolerance Scores

LoFtool: 0.261
RVIS EVS: -0.29
RVIS percentile EVS: 33.2

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.978

Gene Damage Prediction

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