rs753375115
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The ENST00000240851.9(TFG):c.944C>T(p.Pro315Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P315S) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000240851.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TFG | NM_006070.6 | c.944C>T | p.Pro315Leu | missense_variant | 8/8 | ENST00000240851.9 | NP_006061.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TFG | ENST00000240851.9 | c.944C>T | p.Pro315Leu | missense_variant | 8/8 | 1 | NM_006070.6 | ENSP00000240851 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152124Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 250828Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135658
GnomAD4 exome AF: 0.0000438 AC: 64AN: 1461836Hom.: 1 Cov.: 33 AF XY: 0.0000509 AC XY: 37AN XY: 727216
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152124Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74296
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 16, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | TFG: PM2, BP4 - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2024 | The c.944C>T (p.P315L) alteration is located in exon 8 (coding exon 7) of the TFG gene. This alteration results from a C to T substitution at nucleotide position 944, causing the proline (P) at amino acid position 315 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary motor and sensory neuropathy, Okinawa type;C3714897:Hereditary spastic paraplegia 57 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 22, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 315 of the TFG protein (p.Pro315Leu). This variant is present in population databases (rs753375115, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with TFG-related conditions. ClinVar contains an entry for this variant (Variation ID: 534741). 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 TFG 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at