rs766450555
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3PP5
The NM_001244710.2(GFPT1):c.1309T>C(p.Phe437Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F437I) has been classified as Uncertain significance.
Frequency
Consequence
NM_001244710.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GFPT1 | NM_001244710.2 | c.1309T>C | p.Phe437Leu | missense_variant | 14/20 | ENST00000357308.9 | |
GFPT1 | NM_002056.4 | c.1255T>C | p.Phe419Leu | missense_variant | 13/19 | ||
GFPT1 | XM_017003801.2 | c.1384T>C | p.Phe462Leu | missense_variant | 14/20 | ||
GFPT1 | XM_017003802.3 | c.1330T>C | p.Phe444Leu | missense_variant | 13/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GFPT1 | ENST00000357308.9 | c.1309T>C | p.Phe437Leu | missense_variant | 14/20 | 5 | NM_001244710.2 | ||
GFPT1 | ENST00000361060.5 | c.1255T>C | p.Phe419Leu | missense_variant | 13/19 | 1 | P1 | ||
GFPT1 | ENST00000674507.1 | c.1255T>C | p.Phe419Leu | missense_variant | 13/18 | ||||
GFPT1 | ENST00000674438.1 | c.1039T>C | p.Phe347Leu | missense_variant | 11/17 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
GFPT1-related myopathy with protein aggregates and rimmed vacuoles Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire | Mar 01, 2024 | PVS1+PS3+PM2+PP3+PP4+PP5 - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 2020 | The alteration results in an amino acid change:_x000D_ _x000D_ The c.1255T>C (p.F419L) alteration is located in coding exon 13 of the GFPT1 gene. This alteration results from a T to C substitution at nucleotide position 1255, causing the phenylalanine (F) at amino acid position 419 to be replaced by a leucine (L). The alteration is not observed in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the GFPT1 c.1255T>C alteration was not observed, with coverage at this position. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.F419 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.F419L alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Congenital myasthenic syndrome 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 04, 2023 | This variant has not been reported in the literature in individuals affected with GFPT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 437 of the GFPT1 protein (p.Phe437Leu). ClinVar contains an entry for this variant (Variation ID: 986215). 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. 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 GFPT1 protein function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at