rs147740901
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
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. 15/21 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
Consequence
NM_052859.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RFT1 | NM_052859.4 | c.1331C>T | p.Thr444Met | missense_variant | 12/13 | ENST00000296292.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RFT1 | ENST00000296292.8 | c.1331C>T | p.Thr444Met | missense_variant | 12/13 | 1 | NM_052859.4 | P1 | |
RFT1 | ENST00000394738.7 | c.1214C>T | p.Thr405Met | missense_variant | 11/12 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000388 AC: 59AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000467 AC: 115AN: 246182Hom.: 0 AF XY: 0.000513 AC XY: 68AN XY: 132664
GnomAD4 exome AF: 0.000527 AC: 769AN: 1460128Hom.: 4 Cov.: 32 AF XY: 0.000543 AC XY: 394AN XY: 726088
GnomAD4 genome AF: 0.000387 AC: 59AN: 152348Hom.: 0 Cov.: 32 AF XY: 0.000268 AC XY: 20AN XY: 74500
ClinVar
Submissions by phenotype
RFT1-congenital disorder of glycosylation Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 444 of the RFT1 protein (p.Thr444Met). This variant is present in population databases (rs147740901, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with RFT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 547993). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RFT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 30, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2021 | The c.1331C>T (p.T444M) alteration is located in exon 12 (coding exon 12) of the RFT1 gene. This alteration results from a C to T substitution at nucleotide position 1331, causing the threonine (T) at amino acid position 444 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 04, 2020 | Reported in the heterozygous state in a patient with central serous chorioretinopathy who also harbored several variants in other genes (Schellevis et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30724488) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at