GIGYF1

protein-coding

GRB10 interacting GYF protein 1, the group of Armadillo like helical domain containing

Gene summary

This gene encodes a member of the gyf family of adaptor proteins. The encoded protein contains a gyf protein interaction domain. It binds growth factor receptor bound 10, another adaptor protein that binds activated insulin-like growth factor 1 and insulin receptors and regulates receptor signaling. [provided by RefSeq, Apr 2017]

Previous symbols:

PERQ1

MANE transcript

NM_001375765.1

Inheritance

ClinVar variants

P:21U:194B:42

Top phenotype

complex neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr7:100,679,507-100,694,250

External References & Databases

Ensembl (ENSG00000146830)

Transcript & Mutation Effects

hg38 • Region Span ~14.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

autism spectrum disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: PanelApp Australia

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*GIGYF1* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2015 (Krumm et al, PMID: 25961944). Individuals with variants in *GIGYF1* have been reported with neurodevelopmental delays and/or autism spectrum disorder; however, individuals with similar variants have also been observed in the general population or in reportedly unaffected parents of affected individuals. Deep phenotyping of parents in these studies is often unavailable. Twenty six de novo variants (missense, nonsense, frameshift) that have been reported in 26 affected probands in 6 publications (PMIDs: 33057194, 36924980, 31452935, 31981491, 25961944, 28135719) are included in this curation. In view of an uncertain disease mechanism, a tolerance to heterozygous loss-of-function in population databases, and lack of detail on phenotypic features in the large cohort papers referenced, all loss-of-function variants were downgraded from 1.5 points to 0.5 points. This gene-disease relationship is also supported by animal models (PMIDs: 35917186 and 36924980). Heterozygous mouse models showed anxiety and impaired social behaviors, suggestive of autistic behaviors (PMIDs: 35917186 and 36924980). Knockout zebrafish models showed behaviors of anxiety and impaired social interactions, also consistent with autistic behaviors (PMID: 36924980). While the relationship between *GIGYF1* and complex neurodevelopmental disorder has been replicated over time resulting in a Definitive classification, the extent of reduced penetrance and variable expressivity is currently unknown (PMID: 35917186). This classification was approved by the ClinGen Intellectual Disability and Autism GCEP on the meeting date September 14, 2023 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GIGYF1 variants in ClinVar

11 Conditions Cataloged

not specifiedTotal: 187

GIGYF1-related disorderTotal: 53

not providedTotal: 32

Autism spectrum disorderTotal: 8

Neurodevelopmental disorderTotal: 4

Complex neurodevelopmental disorderTotal: 2

Gigyf1-related Developmental DisorderTotal: 1

GIGYF1-associated neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001375765.1. 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			1 clinvar	29 clinvar	5 clinvar	35
missense			170 clinvar	5 clinvar	3 clinvar	178
nonsense	2 clinvar	5 clinvar	7 clinvar			14
start loss						0
frameshift	10 clinvar	3 clinvar	11 clinvar			24
splice donor/acceptor (+/-2bp)		1 clinvar	5 clinvar			6
Total	12	9	194	34	8	257

Highest pathogenic variant AF is 0.000004361657

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 45 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001375765.1	RefSeq	NP_001362694.1	24	MANE Select
ENST00000678049.1	Ensembl	ENSP00000503354.1	24	MANE Select
NM_001375759.1	RefSeq	NP_001362688.1	23	Standard
NM_001375760.1	RefSeq	NP_001362689.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

biological_process
insulin-like growth factor receptor signaling pathway

Molecular Function

protein binding

Cellular Component

protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000275732
Coding exons: 24
Length: 9942
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125748
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.149	656	645	1.02	0.0000450	6579
Missense (PolyPhen)		98	106.49	0.92031		1167
Synonymous	-3.44	352	279	1.26	0.0000195	2073
Loss of Function	4.93	22	64.9	0.339	0.00000364	636

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00053	0.00051	rare
European (Non-Finnish)	0.00022	0.00021	rare
South Asian	0.00010	0.000098	rare
Other	0.00050	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling. May increase IGF1 receptor phosphorylation under IGF1 stimulation as well as phosphorylation of IRS1 and SHC1 (By similarity). {ECO:0000250, ECO:0000269|PubMed:12771153}.;

Recessive Scores

pRec: 0.149

Intolerance Scores

LoFtool: 0.0883
RVIS EVS: -1.66
RVIS percentile EVS: 2.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.768

Gene Damage Prediction

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