ADSS1

protein-coding

adenylosuccinate synthase 1

Gene summary

This gene encodes a member of the adenylosuccinate synthase family of proteins. The encoded muscle-specific enzyme plays a role in the purine nucleotide cycle by catalyzing the first step in the conversion of inosine monophosphate (IMP) to adenosine monophosphate (AMP). Mutations in this gene may cause adolescent onset distal myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

Previous symbols:

ADSSL1

MANE transcript

NM_152328.5

Inheritance

ClinVar variants

P:31U:193B:96

Top phenotype

Myopathy, distal, 5

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr14:104,724,174-104,747,325

External References & Databases

Ensembl (ENSG00000185100)

Transcript & Mutation Effects

hg38 • Region Span ~23.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myopathy, distal, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014877

Submitter: PanelApp Australia

myopathy, distal, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014877

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Myopathy, distal, 5AR

Manifestation: Musculoskeletal

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: 26506222; 28268051; 32331917; 32646962

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ADSS1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 401

Inborn genetic diseasesTotal: 133

Myopathy, distal, 5Total: 35

ADSS1-related disorderTotal: 25

not specifiedTotal: 12

Fetal akinesia deformation sequence 1Total: 1

ADSSL1-related disordersTotal: 1

Arthrogryposis multiplex congenitaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152328.5. 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			1 clinvar	87 clinvar	3 clinvar	91
missense	1 clinvar	3 clinvar	184 clinvar	3 clinvar	3 clinvar	194
nonsense	4 clinvar	1 clinvar				5
start loss						0
frameshift	5 clinvar	4 clinvar	3 clinvar			12
splice donor/acceptor (+/-2bp)	2 clinvar	11 clinvar	5 clinvar			18
Total	12	19	193	90	6	320

Highest pathogenic variant AF is 0.00018038614

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152328.5	RefSeq	NP_689541.1	13	MANE Select
ENST00000330877.7	Ensembl	ENSP00000331260.2	13	MANE Select
NM_001320424.1	RefSeq	NP_001307353.1	7	Standard
NM_199165.2	RefSeq	NP_954634.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
adssl1	Danio rerio	Structure: skeletal muscle cell Quality: apoptotic abnormal

Gene / Model

Organism

Observed Phenotype

adssl1

Danio rerio

Structure: skeletal muscle cell

Quality: apoptotic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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

Biological Process

immune system process
AMP biosynthetic process
aspartate metabolic process
glutamine metabolic process
purine ribonucleoside monophosphate biosynthetic process

Molecular Function

magnesium ion binding
GTPase activity
adenylosuccinate synthase activity
GTP binding
phosphate ion binding

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000332972
Coding exons: 13
Length: 23140
Individuals with no LoFs: 125578
Homozygous LoFs: 2
Heterozygous LoFs: 168
Defined: 125748
p: 0.000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0328	306	304	1.01	0.0000184	3206
Missense (PolyPhen)		148	139.96	1.0574		1315
Synonymous	0.811	117	129	0.909	0.00000874	1007
Loss of Function	2.20	15	27.4	0.547	0.00000145	294

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.0016	0.0016	notable
Ashkenazi Jewish	0.00099	0.00099	rare
East Asian	0.0013	0.0013	notable
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00047	0.00046	rare
South Asian	0.00056	0.00052	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the purine nucleotide cycle (PNC), which interconverts IMP and AMP to regulate the nucleotide levels in various tissues, and which contributes to glycolysis and ammoniagenesis. Catalyzes the first committed step in the biosynthesis of AMP from IMP. {ECO:0000269|PubMed:26506222}.;

Recessive Scores

pRec: 0.155

Intolerance Scores

LoFtool: 0.875
RVIS EVS: -0.02
RVIS percentile EVS: 52.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.683

Gene Damage Prediction

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