rs763862849

chr3-53122376-T-Cchr3-53122376-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K152N) has been classified as Uncertain significance.

• 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

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]

ACMG classification

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/exons	MANE	UniProt
RFT1	NM_052859.4	c.454A>G	p.Lys152Glu	missense_variant, splice_region_variant	4/13	ENST00000296292.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFT1	ENST00000296292.8	c.454A>G	p.Lys152Glu	missense_variant, splice_region_variant	4/13	1	NM_052859.4	P1
RFT1	ENST00000394738.7	c.337A>G	p.Lys113Glu	missense_variant, splice_region_variant	3/12	5
RFT1	ENST00000467048.1	c.454A>G	p.Lys152Glu	missense_variant, splice_region_variant	4/9	3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152176 Hom.: 0 Cov.: 32

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: 13 AN: 251342 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135842

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: 40 AN: 1461624 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 727116

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: 3 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74334

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.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RFT1-congenital disorder of glycosylation Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 19, 2019

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	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	31
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	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.1	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
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	D
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

Other links and lift over

dbSNP: rs763862849; hg19: chr3-53156392;