SLC38A8

protein-coding

solute carrier family 38 member 8, the group of Solute carrier family 38

Gene summary

This gene encodes a putative sodium-dependent amino-acid/proton antiporter. The protein has eleven transmembrane domains, an extracellular N-terminus and an intracellular C-terminal tail. The protein is a member of the SLC38 sodium-coupled neutral amino acid transporter family of proteins. Mutations in this gene result in foveal hypoplasia with or without optic nerve misrouting and/or anterior segment dysgenesis. [provided by RefSeq, May 2014]

MANE transcript

NM_001080442.3

Inheritance

ClinVar variants

P:81U:158B:307

Top phenotype

Foveal hypoplasia 2

gnomAD constraint

pLI —, LoF o/e 1.5

Max pathogenic AF

—

Genomic locus

chr16:84,009,667-84,042,795

External References & Databases

Ensembl (ENSG00000166558)

Transcript & Mutation Effects

hg38 • Region Span ~33.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012216

Submitter: Ambry Genetics

foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012216

Submitter: Labcorp Genetics (formerly Invitae)

foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012216

Submitter: Orphanet

foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012216

Submitter: PanelApp Australia

foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012216

Submitter: ClinGen

*SLC38A8* has been repeatedly associated with autososomal recessive foveal hypoplasia 2 with or without optic nerve misrouting and/or anterior segment dysgenesis, also known as foveal hypoplasia, optic nerve decussation and anterior segment dysgenesis without albinism (FHONDA). Patients with the disorder often present with foveal hypoplasia, nystagmus, reduced visual accuity, and chiasmal misrouting. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 19 variants (frameshift, splice site, nonsense, in-frame deletion, and missense) have been reported in 16 probands from 3 publications (PMID:32744312, PMID:24290379, PMID:24045842). A summed LOD score of 7.06 was calculated from two seperate publications (PMID:24290379, PMID:24045842). The gene *SLC38A8* encodes SNAT8 (sodium coupled neutral amino acid transporter) 8, which is expressed in all neurons and has a broad substrate profile for a number of amino acids. Due to its expression in the central nervous system and as a transporter of glutamine, it may be involved in glutamate/glutamine (GABA) cycling. This gene-disease association is further supported by its biochemical function as an amino acid transporter (PMID:25451601) and in SLC38A8 kock-down Medaka (PMID:24290379), which showed microphthalmia, coloboma, and lens defects. A classification of definitive was reached on 1/27/2022 by the Aminoacidopathy GCEP.

foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012216

Submitter: G2P

Clinical Genomic Database (CGD)

Foveal hypoplasia 2AR

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: 24045842; 24290379

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC38A8 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 586

Inborn genetic diseasesTotal: 127

SLC38A8-related disorderTotal: 48

Foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndromeTotal: 42

not specifiedTotal: 37

FOVEAL HYPOPLASIA 2 WITH OPTIC NERVE MISROUTING AND ANTERIOR SEGMENT DYSGENESISTotal: 2

Foveal hypoplasia 2 and optic nerve misrouting with or without anterior segment dysgenesisTotal: 2

Isolated foveal hypoplasiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080442.3. 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				274 clinvar	10 clinvar	284
missense	3 clinvar	7 clinvar	155 clinvar	18 clinvar	5 clinvar	188
nonsense	11 clinvar	10 clinvar				21
start loss			1 clinvar			1
frameshift	20 clinvar	8 clinvar				28
splice donor/acceptor (+/-2bp)	1 clinvar	21 clinvar	2 clinvar			24
Total	35	46	158	292	15	546

Highest pathogenic variant AF is 0.00018031393

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080442.3	RefSeq	NP_001073911.1	10	MANE Select
ENST00000299709.8	Ensembl	ENSP00000299709.3	10	MANE Select
ENST00000568178.1	Ensembl	ENSP00000457737.1	6	Standard
ENST00000569816.1	Ensembl	ENSP00000455085.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

amino acid transmembrane transport
sodium ion transport

Molecular Function

amino acid transmembrane transporter activity

Cellular Component

integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000299709
Coding exons: 10
Length: 32970
Individuals with no LoFs: 125653
Homozygous LoFs: 0
Heterozygous LoFs: 95
Defined: 125748
p: 0.000378

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-4.34	472	271	1.74	0.0000163	2761
Missense (PolyPhen)		175	104.68	1.6718		1153
Synonymous	-7.31	225	122	1.84	0.00000834	939
Loss of Function	-2.06	30	20.1	1.50	9.54e-7	215

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00080	0.00080	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00071	0.00071	rare
Finnish	0.000092	0.000092	rare
European (Non-Finnish)	0.00027	0.00026	rare
South Asian	0.00072	0.00072	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Putative sodium-dependent amino acid/proton antiporter. {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.885
RVIS EVS: -0.94
RVIS percentile EVS: 9.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.239

Gene Damage Prediction

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