SIPA1L3

protein-coding

signal induced proliferation associated 1 like 3, the group of PDZ domain containing

Gene summary

This gene belongs to the signal induced proliferation associated 1 family of genes, which encode GTPase-activating proteins specific for the GTP-binding protein Rap1. Rap1 has been implicated in regulation of cell adhesion, cell polarity, and organization of the cytoskeleton. Like other members of the family, the protein encoded by this gene contains RapGAP and PDZ domains. In addition, this protein contains a C-terminal leucine zipper domain. This gene is proposed to function in epithelial cell morphogenesis and establishment or maintenance of polarity. Consistently, expression of the protein in cell culture showed localization to cell-cell borders in apical regions, and downregulation of the gene in 3D Caco2 cell culture resulted in abnormal cell polarity and morphogenesis. Allelic variants of this gene have been associated with congenital cataracts in humans. [provided by RefSeq, Feb 2016]

MANE transcript

NM_015073.3

Inheritance

AD, AR, SD

ClinVar variants

P:2U:382B:132

Top phenotype

Cataract 45

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr19:37,907,208-38,208,369

External References & Databases

Ensembl (ENSG00000105738)

Transcript & Mutation Effects

hg38 • Region Span ~301.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

total early-onset cataractSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0021548

Submitter: Orphanet

cataract 45MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014799

Submitter: PanelApp Australia

cataract 45MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014799

Submitter: PanelApp Australia

cataract 45LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014799

Submitter: G2P

cataract 45LIMITED

Inheritance Pattern: SD

Disease ID:MONDO:0014799

Submitter: Ambry Genetics

cataract 45LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014799

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Cataract 45AR

Manifestation: Ophthalmologic

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: 25804400

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SIPA1L3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 352

not providedTotal: 247

SIPA1L3-related disorderTotal: 38

Cataract 45Total: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015073.3. 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			5 clinvar	80 clinvar	13 clinvar	98
missense			373 clinvar	32 clinvar	7 clinvar	412
nonsense	1 clinvar		1 clinvar			2
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	2	0	382	112	20	516

Highest pathogenic variant AF is 0.0000027365097

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015073.3	RefSeq	NP_055888.1	20	MANE Select
ENST00000222345.11	Ensembl	ENSP00000222345.4	20	MANE Select
ENST00000595384.1	Ensembl	ENSP00000468981.1	3	Standard
ENST00000601054.1	Ensembl	ENSP00000472734.2	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
sipa1l3	Danio rerio	Structure: eye Quality: perforate abnormal

Gene / Model

Organism

Observed Phenotype

sipa1l3

Danio rerio

Structure: eye

Quality: perforate

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Rap1 signaling pathway - Homo sapiens (human)

Biological Process

eye development
hematopoietic progenitor cell differentiation
epithelial cell morphogenesis
cytoskeleton organization
positive regulation of GTPase activity

Molecular Function

GTPase activator activity

Cellular Component

stress fiber
extracellular space
apical plasma membrane
apical part of cell
tricellular tight junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000222345
Coding exons: 20
Length: 301145
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.55	1018	1.17e+3	0.872	0.0000805	11499
Missense (PolyPhen)		296	410.29	0.72144		4033
Synonymous	-0.659	555	536	1.04	0.0000421	3721
Loss of Function	6.72	7	65.9	0.106	0.00000352	715

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000070	0.000062	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00019	0.00018	rare
South Asian	0.000099	0.000098	rare
Other	0.00035	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a critical role in epithelial cell morphogenesis, polarity, adhesion and cytoskeletal organization in the lens (PubMed:26231217). {ECO:0000269|PubMed:26231217}.;
Disease: DISEASE: Note=A chromosomal translocation involving SIPA1L3 is found in a patient with bilateral severe ocular abnormalities including congenital cataracts, corneal clouding, iridocorneal and lenticular adhesions and microphthalmia. Chromosomal translocation t(2;19)(q37.3;q13.1). In addition to translocation, missense variant has been found in patient with bilateral congenital cataracts (PubMed:26231217). {ECO:0000269|PubMed:26231217}.; DISEASE: Cataract 45 (CTRCT45) [MIM:616851]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. {ECO:0000269|PubMed:25804400}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.132
RVIS EVS: -1.61
RVIS percentile EVS: 2.95

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.930

Gene Damage Prediction

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