SNF8

protein-coding

SNF8 subunit of ESCRT-II, the group of ESCRT-II

Gene summary

The protein encoded by this gene is a component of the endosomal sorting complex required for transport II (ESCRT-II), which regulates the movement of ubiquitinylated transmembrane proteins to the lysosome for degradation. This complex also interacts with the RNA polymerase II elongation factor (ELL) to overcome the repressive effects of ELL on RNA polymerase II activity. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

MANE transcript

NM_007241.4

Inheritance

ClinVar variants

P:7U:35B:1

Top phenotype

Developmental and epileptic encephalopathy 115; Neurodevelopmental disorder plus optic atrophy

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr17:48,929,316-48,944,842

External References & Databases

Ensembl (ENSG00000159210)

Transcript & Mutation Effects

hg38 • Region Span ~15.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy 115STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0968946

Submitter: PanelApp Australia

neurodevelopmental disorder plus optic atrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0968947

Submitter: G2P

neurodevelopmental disorder plus optic atrophyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0968947

Submitter: PanelApp Australia

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 115; Neurodevelopmental disorder plus optic atrophyAR

Manifestation: Neurologic; 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: 38423010

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SNF8 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 30

SNF8-associated diseaseTotal: 7

Neurodevelopmental disorder plus optic atrophyTotal: 4

Developmental and epileptic encephalopathy 115Total: 4

not providedTotal: 1

Aganglionic megacolonTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_007241.4. 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		1
missense	3 clinvar	1 clinvar	31 clinvar			35
nonsense	1 clinvar					1
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)	1 clinvar		4 clinvar			5
Total	6	1	35	1	0	43

Highest pathogenic variant AF is 0.00016912633

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_007241.4	RefSeq	NP_009172.2	8	MANE Select
ENST00000502492.6	Ensembl	ENSP00000421380.1	8	MANE Select
NM_001317192.2	RefSeq	NP_001304121.1	8	Standard
NM_001317193.2	RefSeq	NP_001304122.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Endocytosis - Homo sapiens (human)
Vesicle-mediated transport
Membrane Trafficking
Endosomal Sorting Complex Required For Transport (ESCRT)

Biological Process

regulation of transcription by RNA polymerase II
positive regulation of gene expression
regulation of multivesicular body size involved in endosome transport
endosomal transport
macroautophagy

Molecular Function

protein binding
protein C-terminus binding
transcription factor binding
channel regulator activity
protein homodimerization activity

Cellular Component

ESCRT II complex
nucleus
nucleoplasm
transcription factor complex
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000502492
Coding exons: 8
Length: 15802
Individuals with no LoFs: 125718
Homozygous LoFs: 0
Heterozygous LoFs: 30
Defined: 125748
p: 0.000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.13	113	152	0.742	0.00000854	1675
Missense (PolyPhen)		19	40.86	0.465		469
Synonymous	-0.331	66	62.7	1.05	0.00000381	500
Loss of Function	1.91	8	16.3	0.489	8.21e-7	178

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00043	0.00044	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000079	0.000079	rare
South Asian	0.00016	0.00016	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the endosomal sorting complex required for transport II (ESCRT-II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs. The MVB pathway mediates delivery of transmembrane proteins into the lumen of the lysosome for degradation. The ESCRT-II complex is probably involved in the recruitment of the ESCRT-III complex. The ESCRT-II complex may also play a role in transcription regulation by participating in derepression of transcription by RNA polymerase II, possibly via its interaction with ELL. Required for degradation of both endocytosed EGF and EGFR, but not for the EGFR ligand-mediated internalization. It is also required for the degradation of CXCR4. Required for the exosomal release of SDCBP, CD63 and syndecan (PubMed:22660413). {ECO:0000269|PubMed:17714434, ECO:0000269|PubMed:17959629, ECO:0000269|PubMed:18031739, ECO:0000269|PubMed:22660413}.;

Recessive Scores

pRec: 0.112

Intolerance Scores

LoFtool: 0.380
RVIS EVS: -0.34
RVIS percentile EVS: 30.07

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.972

Gene Damage Prediction

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