SIPA1

protein-coding

signal-induced proliferation-associated 1, the group of PDZ domain containing|MicroRNA protein coding host genes

Gene summary

The product of this gene is a mitogen induced GTPase activating protein (GAP). It exhibits a specific GAP activity for Ras-related regulatory proteins Rap1 and Rap2, but not for Ran or other small GTPases. This protein may also hamper mitogen-induced cell cycle progression when abnormally or prematurely expressed. It is localized to the perinuclear region. Two alternatively spliced variants encoding the same isoform have been characterized to date. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006747.4

Inheritance

—

ClinVar variants

U:178B:12

Top phenotype

Pyloric stenosis

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr11:65,638,101-65,650,918

External References & Databases

Ensembl (ENSG00000213445)

Transcript & Mutation Effects

hg38 • Region Span ~12.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIPA1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 167

not providedTotal: 4

Pyloric stenosisTotal: 1

Esophageal atresiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006747.4. 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			4 clinvar		1 clinvar	5
missense			167 clinvar	9 clinvar	2 clinvar	178
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	0	0	178	9	3	190

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006747.4	RefSeq	NP_006738.3	15	MANE Select
ENST00000534313.6	Ensembl	ENSP00000436269.1	15	MANE Select
NM_153253.30	RefSeq	NP_694985.29	15	Standard
ENST00000394224.3	Ensembl	ENSP00000377771.3	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Rap1 signaling pathway - Homo sapiens (human)
Leukocyte transendothelial migration - Homo sapiens (human)
MAPK Cascade
Immune System
Rap1 signalling

Biological Process

cytoskeleton organization
negative regulation of cell adhesion
signal transduction
cell population proliferation
negative regulation of cell growth

Molecular Function

GTPase activator activity
protein binding
protein C-terminus binding

Cellular Component

nucleus
cytosol
membrane
transport vesicle
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394224
Coding exons: 15
Length: 12834
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 25
Defined: 125748
p: 0.0000994

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.46	445	617	0.721	0.0000423	6469
Missense (PolyPhen)		139	240.87	0.57707		2460
Synonymous	1.94	237	278	0.852	0.0000196	2310
Loss of Function	3.83	11	35.7	0.308	0.00000176	411

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: GTPase activator for the nuclear Ras-related regulatory proteins Rap1 and Rap2 in vitro, converting them to the putatively inactive GDP-bound state (PubMed:9346962). Affects cell cycle progression (By similarity). {ECO:0000250|UniProtKB:P46062, ECO:0000269|PubMed:9346962}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

RVIS EVS: -0.08
RVIS percentile EVS: 47.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.818

Gene Damage Prediction

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