3-53092605-T-G

Variant names:

• chr3-53092605-T-G
• NM_052859.4:c.1222A>C
• RFT1 p.Met408Leu

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_052859.4(RFT1):​c.1222A>C​(p.Met408Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. M408V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFT1 NM_052859.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.76
• Publications: 0 publications found

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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000272305 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-53092605-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 207990.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFT1	NM_052859.4	MANE Select	c.1222A>C	p.Met408Leu	missense	Exon 12 of 13	NP_443091.1	Q96AA3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFT1	ENST00000296292.8	TSL:1 MANE Select	c.1222A>C	p.Met408Leu	missense	Exon 12 of 13	ENSP00000296292.3	Q96AA3
	ENSG00000272305	ENST00000607283.5	TSL:5	n.85A>C		non_coding_transcript_exon	Exon 2 of 5	ENSP00000475819.1	U3KQE9
	RFT1	ENST00000909797.1		c.1408A>C	p.Met470Leu	missense	Exon 13 of 14	ENSP00000579856.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.072
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.41
Sift	Benign	0.18	T
Sift4G	Benign	0.15	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.84
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-53126621;