RFT1

protein-coding

RFT1 homolog

Gene summary

This gene encodes an enzyme which catalyzes the translocation of the Man(5)GlcNAc (2)-PP-Dol intermediate from the cytoplasmic to the luminal side of the endoplasmic reticulum membrane in the pathway for the N-glycosylation of proteins. Mutations in this gene are associated with congenital disorder of glycosylation type In.[provided by RefSeq, Dec 2008]

MANE transcript

NM_052859.4

Inheritance

ClinVar variants

P:21U:213B:144

Top phenotype

Congenital disorder of glycosylation, type In

gnomAD constraint

pLI —, LoF o/e 0.77

Max pathogenic AF

—

Genomic locus

chr3:53,066,853-53,130,453

External References & Databases

Ensembl (ENSG00000163933)

Transcript & Mutation Effects

hg38 • Region Span ~63.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

RFT1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012783

Submitter: G2P

RFT1-congenital disorder of glycosylationSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012783

Submitter: Orphanet

RFT1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012783

Submitter: Labcorp Genetics (formerly Invitae)

RFT1-congenital disorder of glycosylationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012783

Submitter: ClinGen

RFT1 was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Haeuptle MA, et al. in 2008 (PMID:18313027). At least 15 unique variants (missense and 1 frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental data. Variants in this gene have been reported in at least 15 probands from 12 publications (PMIDs:18313027, 19701946, 1985612, 23111317, 29923091, 27172925, 28940310, 28600779, 36579437, 30071302, 30653653, and 28940097). Patient symptoms mainly include encephalopathy, epilepsy, and hearing impairment as well as variable feeding problems, dysmorphism, Global developmental delay, Type I transferrin isoform profile, and hypotonia. No supporting segregation information is available. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is supported by the biochemical function of RFT1, which is a putative flippase involved in the transfer of Man5GlcNAc2-PP-Dol from the cytoplasmic to the luminal side of the endoplasmic reticulum (PMID: 11807558). Functional alteration of non-patient cells also shows that mutations in the RFT1 gene resulted in variable degrees of impairment in RFT activity and N-linked glycosylation (PMID: 18313027). Finally, rescue in patient cells shows that the expression of the wild-type RFT1 cDNA in the respective patient-derived fibroblasts restored the synthesis of the complete LLO DolPP-GlcNAc2Man9Glc3 (PMID: 22213132). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. A classification of moderate was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 9/06/2023 (SOP Version 9).

RFT1-congenital disorder of glycosylationSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012783

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Congenital disorder of glycosylation, type InAR

Manifestation: Biochemical; Gastrointestinal; Hematologic; Neurologic

Intervention: Hematologic

Rationale: Awareness of coagulopathies may be beneficial in terms of medical management, especially in situations such as surgery

Comments: Hepatic-metabolized agents should be avoided

Refs: 9516657; 10801058; 18313027; 19701946

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFT1 variants in ClinVar

6 Conditions Cataloged

RFT1-congenital disorder of glycosylationTotal: 440

Inborn genetic diseasesTotal: 78

not providedTotal: 49

not specifiedTotal: 23

RFT1-related disorderTotal: 13

RFT1 related CDGTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_052859.4. 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			6 clinvar	127 clinvar		133
missense	5 clinvar	7 clinvar	188 clinvar	16 clinvar	1 clinvar	217
nonsense		2 clinvar	5 clinvar			7
start loss			1 clinvar			1
frameshift		4 clinvar	7 clinvar			11
splice donor/acceptor (+/-2bp)		3 clinvar	6 clinvar			9
Total	5	16	213	143	1	378

Highest pathogenic variant AF is 0.0000848766

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_052859.4	RefSeq	NP_443091.1	13	MANE Select
ENST00000296292.8	Ensembl	ENSP00000296292.3	13	MANE Select
ENST00000394738.7	Ensembl	ENSP00000378223.3	12	Standard
ENST00000394738.8	Ensembl	ENSP00000378223.3	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in leukocytes - TarBase
miR-targeted genes in lymphocytes - TarBase
miR-targeted genes in muscle cell - TarBase
Post-translational protein modification
Metabolism of proteins

Biological Process

carbohydrate transport
glycolipid translocation

Molecular Function

lipid transporter activity

Cellular Component

endoplasmic reticulum membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296292
Coding exons: 13
Length: 41980
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125748
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.967	248	295	0.842	0.0000161	3431
Missense (PolyPhen)		98	111.24	0.88097		1355
Synonymous	0.330	119	124	0.962	0.00000670	1149
Loss of Function	1.15	23	29.8	0.772	0.00000162	320

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00020	0.00020	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00029	0.00028	rare
South Asian	0.00026	0.00026	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in N-linked oligosaccharide assembly. May participate in the translocation of oligosaccharide from the cytoplasmic side to the lumenal side of the endoplasmic reticulum membrane. {ECO:0000269|PubMed:18313027}.;
Disease: DISEASE: Congenital disorder of glycosylation 1N (CDG1N) [MIM:612015]: A form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. {ECO:0000269|PubMed:18313027, ECO:0000269|PubMed:19701946}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0959

Intolerance Scores

LoFtool: 0.227
RVIS EVS: 0.09
RVIS percentile EVS: 60.57

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.0453

Gene Damage Prediction

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