SPG21

protein-coding

SPG21 abhydrolase domain containing, maspardin, the group of Abhydrolase domain containing

Gene summary

The protein encoded by this gene binds to the hydrophobic C-terminal amino acids of CD4 which are involved in repression of T cell activation. The interaction with CD4 is mediated by the noncatalytic alpha/beta hydrolase fold domain of this protein. It is thus proposed that this gene product modulates the stimulatory activity of CD4. Mutations in this gene are associated with autosomal recessive spastic paraplegia 21 (SPG21), also known as mast syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

MANE transcript

NM_016630.7

Inheritance

ClinVar variants

P:14U:67B:36

Top phenotype

Spastic paraplegia 21 (Mast syndrome)

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr15:64,963,022-64,990,310

External References & Databases

Ensembl (ENSG00000090487)

Transcript & Mutation Effects

hg38 • Region Span ~27.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mast syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009568

Submitter: PanelApp Australia

mast syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009568

Submitter: Labcorp Genetics (formerly Invitae)

mast syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009568

Submitter: Orphanet

mast syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009568

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spastic paraplegia 21 (Mast syndrome)AR

Manifestation: 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: 6024251; 14564668; 20301682; 24451228

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPG21 variants in ClinVar

5 Conditions Cataloged

Mast syndromeTotal: 87

not providedTotal: 40

not specifiedTotal: 36

Hereditary spastic paraplegiaTotal: 20

SPG21-related disorderTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016630.7. 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			4 clinvar	34 clinvar		38
missense	1 clinvar		54 clinvar	2 clinvar		57
nonsense		3 clinvar				3
start loss			1 clinvar			1
frameshift	5 clinvar	3 clinvar				8
splice donor/acceptor (+/-2bp)		2 clinvar	8 clinvar			10
Total	6	8	67	36	0	117

Highest pathogenic variant AF is 0.00012391066

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 112 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016630.7	RefSeq	NP_057714.1	8	MANE Select
ENST00000204566.7	Ensembl	ENSP00000204566.2	8	MANE Select
NM_001127889.5	RefSeq	NP_001121361.1	8	Standard
NM_001127890.5	RefSeq	NP_001121362.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)

Biological Process

antigen receptor-mediated signaling pathway

Molecular Function

protein binding
CD4 receptor binding

Cellular Component

Golgi apparatus
cytosol
endosome membrane
trans-Golgi network transport vesicle
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000204566
Coding exons: 8
Length: 27287
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.16	127	169	0.749	0.00000883	2035
Missense (PolyPhen)		29	48.014	0.60399		624
Synonymous	-0.506	66	61.0	1.08	0.00000351	570
Loss of Function	2.07	8	17.3	0.462	9.05e-7	196

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00012	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.000065	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role as a negative regulatory factor in CD4- dependent T-cell activation. {ECO:0000269|PubMed:11113139}.;

Recessive Scores

pRec: 0.237

Intolerance Scores

LoFtool: 0.481
RVIS EVS: -0.18
RVIS percentile EVS: 39.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.925

Gene Damage Prediction

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