rs796053522

Variant names:

• chr3-53092605-T-A
• rs796053522
• NM_052859.4:c.1222A>T

Your query was ambiguous. Multiple possible variants found:

• chr3-53092605-T-A
• chr3-53092605-T-C

Variant summary

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

The ENST00000296292.8(RFT1):​c.1222A>T​(p.Met408Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,459,392 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RFT1 ENST00000296292.8 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: PanelApp Australia, ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

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: ENST00000296292.8. 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.1222A>T	p.Met408Leu	missense	Exon 12 of 13	NP_443091.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFT1	ENST00000296292.8	TSL:1 MANE Select	c.1222A>T	p.Met408Leu	missense	Exon 12 of 13	ENSP00000296292.3
	ENSG00000272305	ENST00000607283.5	TSL:5	n.85A>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000475819.1
	RFT1	ENST00000394738.7	TSL:5	c.1105A>T	p.Met369Leu	missense	Exon 11 of 12	ENSP00000378223.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459392 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 725640

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44392

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 85412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111140

Other (OTH) AF: 0.00 AC: 0 AN: 60332

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	0.99	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
Polyphen		0.26	B
Vest4		0.49
MutPred		0.68		Gain of catalytic residue at M408 (P = 0.2661)
MVP		0.88
MPC		0.30
ClinPred		0.89	D
GERP RS		3.9
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)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs796053522; hg19: chr3-53126621;