YWHAG

protein-coding

tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma, the group of 14-3-3 phospho-serine/phospho-threonine binding proteins

Gene summary

This gene product belongs to the 14-3-3 family of proteins which mediate signal transduction by binding to phosphoserine-containing proteins. This highly conserved protein family is found in both plants and mammals, and this protein is 100% identical to the rat ortholog. It is induced by growth factors in human vascular smooth muscle cells, and is also highly expressed in skeletal and heart muscles, suggesting an important role for this protein in muscle tissue. It has been shown to interact with RAF1 and protein kinase C, proteins involved in various signal transduction pathways. [provided by RefSeq, Jul 2008]

MANE transcript

NM_012479.4

Inheritance

ClinVar variants

P:34U:90B:102

Top phenotype

Developmental and epileptic encephalopathy 56

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr7:76,326,799-76,358,991

External References & Databases

Ensembl (ENSG00000170027)

Transcript & Mutation Effects

hg38 • Region Span ~32.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 56DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0033365

Submitter: Illumina

undetermined early-onset epileptic encephalopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: G2P

developmental and epileptic encephalopathy, 56STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033365

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 56STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033365

Submitter: Labcorp Genetics (formerly Invitae)

undetermined early-onset epileptic encephalopathySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018614

Submitter: Orphanet

developmental and epileptic encephalopathy, 56STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033365

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 56AD

Manifestation: Musculoskeletal; 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: 28777935

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to YWHAG variants in ClinVar

17 Conditions Cataloged

not providedTotal: 208

Developmental and epileptic encephalopathy, 56Total: 23

Inborn genetic diseasesTotal: 14

not specifiedTotal: 13

YWHAG-related disorderTotal: 8

SeizureTotal: 3

Bilateral tonic-clonic seizureTotal: 1

SpasticityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012479.4. 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			1 clinvar	93 clinvar	4 clinvar	98
missense	7 clinvar	9 clinvar	75 clinvar	4 clinvar	1 clinvar	96
nonsense	7 clinvar	2 clinvar	6 clinvar			15
start loss		1 clinvar	1 clinvar			2
frameshift	6 clinvar	2 clinvar	6 clinvar			14
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	20	14	90	97	5	226

Highest pathogenic variant AF is 6.843428e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 4 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012479.4	RefSeq	NP_036611.2	2	MANE Select
ENST00000307630.5	Ensembl	ENSP00000306330.3	2	MANE Select
ENST00001124344.1	Ensembl	ENSP00000794149.1	2	Standard
ENST00001139738.1	Ensembl	ENSP00000805823.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ywhag1	Danio rerio	Structure: head Quality: hypoplastic abnormal

Gene / Model

Organism

Observed Phenotype

ywhag1

Danio rerio

Structure: head

Quality: hypoplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
Cell cycle - Homo sapiens (human)
Oocyte meiosis - Homo sapiens (human)
Hippo signaling pathway - Homo sapiens (human)
Viral carcinogenesis - Homo sapiens (human)

Biological Process

G2/M transition of mitotic cell cycle
negative regulation of protein kinase activity
protein targeting
regulation of signal transduction
regulation of G2/M transition of mitotic cell cycle

Molecular Function

RNA binding
protein kinase C binding
insulin-like growth factor receptor binding
protein binding
protein kinase C inhibitor activity

Cellular Component

mitochondrion
cytosol
focal adhesion
membrane
myelin sheath

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000307630
Coding exons: 2
Length: 32233
Individuals with no LoFs: 125727
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125728
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.95	54	159	0.341	0.0000108	1636
Missense (PolyPhen)		8	63.327	0.12633		675
Synonymous	-1.71	91	72.5	1.26	0.00000593	465
Loss of Function	2.98	0	10.3	0.00	6.44e-7	107

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. {ECO:0000269|PubMed:16511572}.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 56 (EIEE56) [MIM:617665]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE56 is an autosomal dominant condition. {ECO:0000269|PubMed:28777935}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.533

Intolerance Scores

RVIS EVS: -0.3
RVIS percentile EVS: 32.62

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.897

Gene Damage Prediction

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