NM_052859.4:c.1331C>T

Variant names:

• chr3-53092496-G-A
• rs147740901
• NM_052859.4:c.1331C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_052859.4(RFT1):​c.1331C>T​(p.Thr444Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,612,476 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T444T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: RFT1 NM_052859.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 1.47
• Publications: 1 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ENSG00000272305 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05360976).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000387 (59/152348) while in subpopulation NFE AF = 0.000735 (50/68030). AF 95% confidence interval is 0.000572. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.1331C>T	p.Thr444Met	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.1331C>T	p.Thr444Met	missense	Exon 12 of 13	ENSP00000296292.3	Q96AA3
	ENSG00000272305	ENST00000607283.5	TSL:5	n.194C>T		non_coding_transcript_exon	Exon 2 of 5	ENSP00000475819.1	U3KQE9
	RFT1	ENST00000909797.1		c.1517C>T	p.Thr506Met	missense	Exon 13 of 14	ENSP00000579856.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000467 AC: 115 AN: 246182 AF XY: 0.000513

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000710

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000527 AC: 769 AN: 1460128 Hom.: 4 Cov.: 32 AF XY: 0.000543 AC XY: 394 AN XY: 726088

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.000337 AC: 15 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25894

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39670

South Asian (SAS) AF: 0.000351 AC: 30 AN: 85552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5764

European-Non Finnish (NFE) AF: 0.000603 AC: 670 AN: 1111560

Other (OTH) AF: 0.000613 AC: 37 AN: 60336

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20 AN XY: 74500

African (AFR) AF: 0.000120 AC: 5 AN: 41584

American (AMR) AF: 0.000196 AC: 3 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000735 AC: 50 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000630 Hom.: 0

Bravo AF: 0.000370

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	RFT1-congenital disorder of glycosylation (5)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.054	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.25
Sift	Benign	0.086	T
Sift4G	Benign	0.087	T
Polyphen		0.045	B
Vest4		0.41
MVP		0.81
MPC		0.14
ClinPred		0.0087	T
GERP RS		4.5
Varity_R		0.020
gMVP		0.34
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs147740901; hg19: chr3-53126512;