ASNS

protein-coding

asparagine synthetase (glutamine-hydrolyzing)

Gene summary

The protein encoded by this gene is involved in the synthesis of asparagine. This gene complements a mutation in the temperature-sensitive hamster mutant ts11, which blocks progression through the G1 phase of the cell cycle at nonpermissive temperature. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2010]

MANE transcript

NM_001673.5

Inheritance

ClinVar variants

P:202U:220B:235

Top phenotype

Asparagine synthetase deficiency

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr7:97,851,677-97,872,542

External References & Databases

Ensembl (ENSG00000070669)

Transcript & Mutation Effects

hg38 • Region Span ~20.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014258

Submitter: Labcorp Genetics (formerly Invitae)

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014258

Submitter: Natera

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014258

Submitter: PanelApp Australia

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014258

Submitter: Orphanet

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014258

Submitter: ClinGen

ASNS was first reported in relation to autosomal recessive asparagine synthetase deficiency in 2013 (Ruzzo et al., PMID: 24139043). Individuals with mutations in the ASNS gene exhibit developmental delays, intellectual disability, microcephaly, intractable seizures, and progressive brain atrophy. Currently, the disease requires molecular diagnosis as some, but not all, affected individuals have a measurable decrease in the amount of asparagine in their serum or cerebrospinal fluid, which limits this analysis as a preliminary screen in suspected cases. At least 24 unique variants (primarily missense but also frameshift and nonsense) 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 22 probands in 15 publications (PMIDs: 29375865, 25663424, 25227173, 29405484, 28776279, 30315573, 26318253, 24139043, 29279279, 30057589, 27422383, 27711071, 27469131, 27743885, 26395554). Variants in this gene segregated with disease in 10 additional family members. Molecular modeling using the Escherichia coli ASNS-B structure has revealed that most of the reported ASD substitutions are located near catalytic sites or within highly conserved regions of the protein (Reviewed in PMID: 29084849). This gene-disease association is supported by its biochemical function in asparagine synthesis, the functional alteration in patient cells resulting in decreased proliferation, the pattern of expression in the brain similar to that of known microcephaly genes, and a hypomorphic mouse model which recapitulates the human brain phenotypes. In summary, ASNS is definitively associated with autosomal recessive inheritance of asparagine synthetase deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014258

Submitter: G2P

Clinical Genomic Database (CGD)

Asparagine synthetase deficiencyAR

Manifestation: Biochemical; 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: 24139043; 27469131; 28776279; 29279279

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASNS variants in ClinVar

9 Conditions Cataloged

not providedTotal: 695

Congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndromeTotal: 199

Inborn genetic diseasesTotal: 64

not specifiedTotal: 39

ASNS-related disorderTotal: 19

Abnormal cerebral morphologyTotal: 3

Neurodevelopmental delayTotal: 2

Neurodevelopmental abnormalityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001673.5. 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			7 clinvar	225 clinvar	1 clinvar	233
missense	6 clinvar	37 clinvar	211 clinvar	9 clinvar		263
nonsense	16 clinvar	21 clinvar	2 clinvar			39
start loss	2 clinvar	2 clinvar				4
frameshift	56 clinvar	30 clinvar				86
splice donor/acceptor (+/-2bp)	2 clinvar	30 clinvar				32
Total	82	120	220	234	1	657

Highest pathogenic variant AF is 0.000043372656

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 72 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001673.5	RefSeq	NP_001664.3	11	MANE Select
ENST00000394308.8	Ensembl	ENSP00000377845.3	11	MANE Select
NM_001178075.2	RefSeq	NP_001171546.1	11	Standard
NM_001178076.2	RefSeq	NP_001171547.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alanine, aspartate and glutamate metabolism - Homo sapiens (human)
Ammonia Recycling
Hypoacetylaspartia
Aspartate Metabolism
Canavan Disease

Biological Process

liver development
asparagine biosynthetic process
glutamine metabolic process
cellular amino acid biosynthetic process
response to light stimulus

Molecular Function

asparagine synthase (glutamine-hydrolyzing) activity
protein binding
ATP binding
protein homodimerization activity
cofactor binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000175506
Coding exons: 11
Length: 20425
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.86	220	312	0.704	0.0000168	3694
Missense (PolyPhen)		60	97.587	0.61484		1291
Synonymous	1.02	99	113	0.878	0.00000616	1050
Loss of Function	2.62	13	27.9	0.466	0.00000145	352

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Disease: DISEASE: Asparagine synthetase deficiency (ASNSD) [MIM:615574]: An inborn error of asparagine biosynthesis that results in a severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. {ECO:0000269|PubMed:24139043}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.260

Intolerance Scores

LoFtool: 0.926
RVIS EVS: -0.03
RVIS percentile EVS: 51.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.949

Gene Damage Prediction

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