rs763862849

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_052859.4(RFT1):c.454A>G(p.Lys152Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000266 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

RFT1
NM_052859.4 missense, splice_region

Scores

Splicing: ADA: 0.5325

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 6.96

Variant links:

Genes affected

RFT1 (HGNC:30220): (RFT1 homolog) 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]

RFT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 3-53122376-T-C is Pathogenic according to our data. Variant chr3-53122376-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 207986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFT1	NM_052859.4 link	c.454A>G	p.Lys152Glu	missense_variant, splice_region_variant	Exon 4 of 13	ENST00000296292.8	NP_443091.1	Q96AA3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RFT1	ENST00000296292.8 link	c.454A>G	p.Lys152Glu	missense_variant, splice_region_variant	Exon 4 of 13	1	NM_052859.4	ENSP00000296292.3	Q96AA3
RFT1	ENST00000394738.7 link	c.337A>G	p.Lys113Glu	missense_variant, splice_region_variant	Exon 3 of 12	5		ENSP00000378223.3	B5MDE0
RFT1	ENST00000467048.1 link	c.454A>G	p.Lys152Glu	missense_variant, splice_region_variant	Exon 4 of 9	3		ENSP00000420325.1	C9JP01

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251342

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461624

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000278

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RFT1-congenital disorder of glycosylation

Pathogenic:3

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 152 of the RFT1 protein (p.Lys152Glu). This variant is present in population databases (rs763862849, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of RFT1-related conditions (PMID: 19701946, 19856127, 26892341, 27172925). ClinVar contains an entry for this variant (Variation ID: 207986). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Dec 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Jun 19, 2019

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the RFT1 gene demonstrated a sequence change, c.454A>G, in exon 4 that results in an amino acid change, p.Lys152Glu. This sequence change has been previously described in two patients in the homozygous state with neurological and clinical features of RFT1-related disorder (PMIDs: 19856127, 19701946). Expression of wild-type RFT1 in the patients? fibroblasts showed complementation of the abnormal lipid-linked oligosaccharide profile and reduced DNase 1 secretion, supporting RFT1 defect (PMID: 19701946). This sequence change has been described in the gnomAD database with a low population frequency of 0.0052% (dbSNP rs763862849). The p.Lys152Glu change affects a highly conserved amino acid residue located in a domain of the RFT1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Lys152Glu substitution. These collective evidences indicate that this sequence change is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.97

D;D;D

MetaSVM

Uncertain

0.66

MutationAssessor

Pathogenic

3.1

M;.;.

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0080

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.97

MutPred

0.90

Loss of ubiquitination at K152 (P = 0.0283);.;Loss of ubiquitination at K152 (P = 0.0283);

MVP

0.94

MPC

0.67

ClinPred

0.67

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.59

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.52

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over