Genetic Variant NM_052859.4:c.454A>C (chr3-53122376-T-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_052859.4(RFT1):c.454A>C(p.Lys152Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000616 in 1,461,624 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K152E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

RFT1
NM_052859.4 missense, splice_region

Scores

Splicing: ADA: 0.8112

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.96

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

RFT1-congenital disorder of glycosylation
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

RFT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-53122376-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 207986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.829

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052859.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFT1	NM_052859.4	MANE Select	c.454A>C	p.Lys152Gln	missense splice_region	Exon 4 of 13	NP_443091.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RFT1	ENST00000296292.8	TSL:1 MANE Select	c.454A>C	p.Lys152Gln	missense splice_region	Exon 4 of 13	ENSP00000296292.3
RFT1	ENST00000394738.7	TSL:5	c.337A>C	p.Lys113Gln	missense splice_region	Exon 3 of 12	ENSP00000378223.3
RFT1	ENST00000850556.1		c.454A>C	p.Lys152Gln	missense splice_region	Exon 4 of 13	ENSP00000520849.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251342

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461624

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000809

AC:

AN:

1111838

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.55

MutationAssessor

Uncertain

2.8

PhyloP100

7.0

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.78

Sift

Benign

0.061

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.95

MVP

0.94

MPC

0.58

ClinPred

0.94

GERP RS

6.0

Varity_R

0.41

gMVP

0.74

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.81

dbscSNV1_RF

Benign

0.58

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over