SPR

sepiapterin reductase, the group of Short chain dehydrogenase/reductase superfamily

Basic information

Region (hg38): 2:72887382-72892158

Links

ENSG00000116096 ∙ NCBI:6697 ∙ OMIM:182125 ∙ HGNC:11257 ∙ Uniprot:P35270 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• dopa-responsive dystonia due to sepiapterin reductase deficiency (Definitive), mode of inheritance: AR
• dopa-responsive dystonia due to sepiapterin reductase deficiency (Moderate), mode of inheritance: AD
• dopa-responsive dystonia due to sepiapterin reductase deficiency (Strong), mode of inheritance: AR
• dopa-responsive dystonia due to sepiapterin reductase deficiency (Strong), mode of inheritance: AR
• dopa-responsive dystonia due to sepiapterin reductase deficiency (Supportive), mode of inheritance: AR
• BH4-deficient hyperphenylalaninemia A (Strong), mode of inheritance: AR
• dopa-responsive dystonia due to sepiapterin reductase deficiency (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Dystonia, Dopa-responsive, due to sepiapterin reductase deficiency	AR	Biochemical	The condition may be frequently mistaken for nonspecific findings such as idiopathic "cerebral palsy", and many individuals benefit from medical therapy (eg, levodopa/carbidopa, 5-hydroxytryptophan)	Biochemical; Neurologic	11443547; 7159114; 18502672; 19130291; 20222129; 21431957; 22291068; 22522443; 22018912; 26123188

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPR gene.

• Dystonic disorder (10 variants)
• Dopa-responsive dystonia due to sepiapterin reductase deficiency (6 variants)
• not provided (4 variants)
• Intellectual disability (1 variants)
• Inborn genetic diseases (1 variants)
• SPR-related disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPR gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	83	1	85
missense	2	2	77			81
nonsense	6	3				9
start loss		2				2
frameshift	5	1				6
inframe indel						0
splice donor/acceptor (+/-2bp)	2		1			3
splice region			2	3		5
non coding			13	17	5	35
Total	15	8	92	100	6

Highest pathogenic variant AF is 0.0000591

Variants in SPR

This is a list of pathogenic ClinVar variants found in the SPR region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-72887393-C-G		Dopa-responsive dystonia	Uncertain significance (Jun 14, 2016)
2-72887419-CGGA-C		Dystonic disorder	Uncertain significance (Feb 22, 2022)
2-72887420-G-A		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Uncertain significance (Jul 01, 2024)
2-72887426-C-G		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Benign/Likely benign (Oct 08, 2021)
2-72887429-G-C		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Uncertain significance (Jan 12, 2018)
2-72887433-A-C		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Likely pathogenic (Mar 01, 2022)
2-72887433-A-G		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Likely pathogenic (Mar 26, 2024)
2-72887436-G-T			Likely pathogenic (Jun 02, 2022)
2-72887438-G-A		Dystonic disorder	Likely benign (Oct 17, 2023)
2-72887437-A-AGGGCGGGCTG		Dystonic disorder	Pathogenic (Oct 22, 2023)
2-72887441-C-T		Dystonic disorder	Likely benign (Nov 21, 2023)
2-72887442-G-A		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Uncertain significance (Jan 22, 2021)
2-72887443-G-T		Dystonic disorder	Uncertain significance (Oct 19, 2021)
2-72887447-G-A		Dystonic disorder	Likely benign (Jan 11, 2024)
2-72887448-G-C		Dystonic disorder • Dopa-responsive dystonia due to sepiapterin reductase deficiency	Uncertain significance (Apr 04, 2022)
2-72887449-G-GGGGGCGGGCT		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Likely pathogenic (Jan 01, 2015)
2-72887455-C-T		Dopa-responsive dystonia due to sepiapterin reductase deficiency • Dystonic disorder	Uncertain significance (Dec 02, 2021)
2-72887456-T-G		Dystonic disorder	Likely benign (Feb 19, 2023)
2-72887459-G-A		Dystonic disorder	Likely benign (Apr 13, 2023)
2-72887460-T-C		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Uncertain significance (Aug 20, 2020)
2-72887470-C-T		Dystonic disorder	Uncertain significance (Apr 20, 2022)
2-72887471-C-G		Dystonic disorder	Likely benign (Dec 11, 2023)
2-72887471-C-T		Dystonic disorder	Likely benign (Dec 12, 2023)
2-72887471-CG-C		Dopa-responsive dystonia due to sepiapterin reductase deficiency	Likely pathogenic (May 30, 2021)
2-72887471-C-CG		Dystonic disorder	Pathogenic (Sep 19, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SPR	protein_coding	protein_coding	ENST00000234454	3	4799

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.0434	0.858	125722	0	25	125747	0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.733	100	123	0.814	0.00000667	1607
Missense in Polyphen		36	44.213	0.81424		551
Synonymous	1.17	49	60.6	0.809	0.00000362	591
Loss of Function	1.35	3	6.80	0.441	3.74e-7	77

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000208	0.000208
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000967	0.0000967
Middle Eastern	0.0000544	0.0000544
South Asian	0.000257	0.0000980
Other	0.000326	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Catalyzes the final one or two reductions in tetra- hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
• Disease: DISEASE: Dystonia, DOPA-responsive, due to sepiapterin reductase deficiency (DRDSPRD) [MIM:612716]: A form of DOPA-responsive dystonia. In the majority of cases, patients manifest progressive psychomotor retardation, dystonia and spasticity. Cognitive anomalies are also often present. The disease is due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Dystonia is defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. {ECO:0000269|PubMed:11443547, ECO:0000269|PubMed:16650784, ECO:0000269|PubMed:17159114}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Folate biosynthesis - Homo sapiens (human);Sepiapterin reductase deficiency;Segawa syndrome;Pterine Biosynthesis;Dopa-responsive dystonia;Hyperphenylalaniemia due to guanosine triphosphate cyclohydrolase deficiency;Hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency (ptps);Hyperphenylalaninemia due to dhpr-deficiency;tetrahydrobiopterin <i>de novo</i> biosynthesis;Metabolism of nitric oxide;Folate metabolism;eNOS activation;eNOS activation and regulation;Metabolism;Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation;Metabolism of cofactors;Metabolism of vitamins and cofactors (Consensus)

Recessive Scores

• pRec: 0.228

Haploinsufficiency Scores

• pHI: 0.151
• hipred: N
• hipred_score: 0.208
• ghis: 0.466

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.992

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Spr
• Phenotype: homeostasis/metabolism phenotype; growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: tetrahydrobiopterin biosynthetic process;nitric oxide biosynthetic process;regulation of nitric-oxide synthase activity;cofactor metabolic process;oxidation-reduction process
• Cellular component: nucleoplasm;cytosol;extracellular exosome
• Molecular function: aldo-keto reductase (NADP) activity;sepiapterin reductase activity;NADP binding