REPS1

protein-coding

RALBP1 associated Eps domain containing 1, the group of EF-hand domain containing

Gene summary

This gene encodes a signaling adaptor protein with two EH domains that interacts with proteins that participate in signaling, endocytosis and cytoskeletal changes. The encoded protein has been found in association with intersectin 1 and Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 when intersectin 1 was isolated from clathrin-coated pits. The encoded protein has also been shown to interact with amphiphysin, a cytoplasmic protein at the surface of synaptic vesicles. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2014]

MANE transcript

NM_001286611.2

Inheritance

ClinVar variants

P:2U:155B:69

Top phenotype

Neurodegeneration with brain iron accumulation 7

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr6:138,903,493-138,988,261

External References & Databases

Ensembl (ENSG00000135597)

Transcript & Mutation Effects

hg38 • Region Span ~84.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodegeneration with brain iron accumulation 7LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0054763

Submitter: PanelApp Australia

neurodegeneration with brain iron accumulation 7LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0054763

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Neurodegeneration with brain iron accumulation 7AR

Manifestation: 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: 29395073

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to REPS1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 215

not specifiedTotal: 83

REPS1-related disorderTotal: 10

Neurodegeneration with brain iron accumulation 7Total: 6

Neurodegeneration with brain iron accumulationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001286611.2. 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			4 clinvar	53 clinvar	5 clinvar	62
missense	1 clinvar	1 clinvar	144 clinvar	10 clinvar	1 clinvar	157
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	1	1	155	63	6	226

Highest pathogenic variant AF is 0.000189091

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 110 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001286611.2	RefSeq	NP_001273540.1	20	MANE Select
ENST00000450536.7	Ensembl	ENSP00000392065.2	20	MANE Select
NM_001128617.3	RefSeq	NP_001122089.1	19	Standard
NM_001286612.2	RefSeq	NP_001273541.1	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Clathrin-mediated endocytosis
Cargo recognition for clathrin-mediated endocytosis

Biological Process

receptor-mediated endocytosis
membrane organization

Molecular Function

calcium ion binding
protein binding
SH3 domain binding

Cellular Component

cytosol
plasma membrane
clathrin-coated pit

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258062
Coding exons: 20
Length: 84769
Individuals with no LoFs: 125733
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125747
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.70	331	430	0.770	0.0000222	5149
Missense (PolyPhen)		123	213.81	0.57527		2661
Synonymous	0.827	140	153	0.915	0.00000819	1602
Loss of Function	5.14	7	43.6	0.160	0.00000209	518

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.000034	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May coordinate the cellular actions of activated EGF receptors and Ral-GTPases. {ECO:0000250}.;
Disease: DISEASE: Neurodegeneration with brain iron accumulation 7 (NBIA7) [MIM:617916]: A neurodegenerative disorder associated with iron accumulation, primarily in the basal ganglia. Clinical features include speech and motor delay, truncal hypotonia, progressive cerebellar ataxia, and loss of ambulation. NBIA7 transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:29395073}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.122

Intolerance Scores

LoFtool: 0.462
RVIS EVS: -0.13
RVIS percentile EVS: 43.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.923

Gene Damage Prediction

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