SRGAP1

protein-coding

SLIT-ROBO Rho GTPase activating protein 1, the group of AH/BAR family Rho GTPase activating proteins|F-BAR domain containing

Gene summary

The protein encoded by this gene is a GTPase activator, working with the GTPase CDC42 to negatively regulate neuronal migration. The encoded protein interacts with the transmembrane receptor ROBO1 to inactivate CDC42. [provided by RefSeq, Sep 2016]

MANE transcript

NM_020762.4

Inheritance

ClinVar variants

P:1U:131B:30

Top phenotype

SRGAP1-related disorder

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr12:63,843,761-64,162,217

External References & Databases

Ensembl (ENSG00000196935)

Transcript & Mutation Effects

hg38 • Region Span ~318.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital anomaly of kidney and urinary tractMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019719

Submitter: PanelApp Australia

thyroid cancer, nonmedullary, 2NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0008566

Submitter: Labcorp Genetics (formerly Invitae)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SRGAP1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 105

not providedTotal: 32

SRGAP1-related disorderTotal: 26

Thyroid cancer, nonmedullary, 2Total: 9

Congenital anomaly of kidney and urinary tractTotal: 3

NephronophthisisTotal: 1

Congenital anomalies of kidney and urinary tract 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020762.4. 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			2 clinvar	18 clinvar	7 clinvar	27
missense	1 clinvar		121 clinvar	3 clinvar	2 clinvar	127
nonsense			1 clinvar			1
start loss						0
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	1	0	131	21	9	162

Highest pathogenic variant AF is 0.000007532616

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020762.4	RefSeq	NP_065813.1	22	MANE Select
ENST00000355086.8	Ensembl	ENSP00000347198.3	22	MANE Select
NM_001346201.2	RefSeq	NP_001333130.1	22	Standard
ENST00000631006.3	Ensembl	ENSP00000485752.2	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Axon guidance - Homo sapiens (human)
Developmental Biology
Signal Transduction
Rho GTPase cycle
Inactivation of CDC42 and RAC1

Biological Process

signal transduction
negative regulation of cell migration
positive regulation of GTPase activity
regulation of small GTPase mediated signal transduction

Molecular Function

GTPase activator activity
protein binding
Rac GTPase binding

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000355086
Coding exons: 22
Length: 303541
Individuals with no LoFs: 125729
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125746
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.21	454	607	0.748	0.0000330	7204
Missense (PolyPhen)		90	150.86	0.59656		1767
Synonymous	1.39	202	229	0.883	0.0000130	2019
Loss of Function	5.81	8	54.1	0.148	0.00000293	654

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000072	0.000070	rare
South Asian	0.00013	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: GTPase-activating protein for RhoA and Cdc42 small GTPases. Together with CDC42 seems to be involved in the pathway mediating the repulsive signaling of Robo and Slit proteins in neuronal migration. SLIT2, probably through interaction with ROBO1, increases the interaction of SRGAP1 with ROBO1 and inactivates CDC42. {ECO:0000269|PubMed:11672528}.;
Disease: DISEASE: Thyroid cancer, non-medullary, 2 (NMTC2) [MIM:188470]: A form of non-medullary thyroid cancer (NMTC), a cancer characterized by tumors originating from the thyroid follicular cells. NMTCs represent approximately 95% of all cases of thyroid cancer and are classified into papillary, follicular, Hurthle cell, and anaplastic neoplasms. {ECO:0000269|PubMed:23539728}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.136

Intolerance Scores

LoFtool: 0.610
RVIS EVS: -0.82
RVIS percentile EVS: 12.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.503

Gene Damage Prediction

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