chr17-44352375-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_002087.4(GRN):c.1448C>T(p.Pro483Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_002087.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GRN | ENST00000053867.8 | c.1448C>T | p.Pro483Leu | missense_variant | Exon 12 of 13 | 1 | NM_002087.4 | ENSP00000053867.2 | ||
GRN | ENST00000589265.5 | c.977C>T | p.Pro326Leu | missense_variant | Exon 8 of 9 | 5 | ENSP00000467616.1 | |||
GRN | ENST00000586443.1 | c.887C>T | p.Pro296Leu | missense_variant | Exon 7 of 7 | 3 | ENSP00000465673.1 | |||
GRN | ENST00000586242.1 | c.80C>T | p.Pro27Leu | missense_variant | Exon 2 of 3 | 3 | ENSP00000467837.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250798Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135678
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461366Hom.: 0 Cov.: 34 AF XY: 0.00000825 AC XY: 6AN XY: 727018
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152242Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74370
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.1448C>T (p.P483L) alteration is located in exon 12 (coding exon 11) of the GRN gene. This alteration results from a C to T substitution at nucleotide position 1448, causing the proline (P) at amino acid position 483 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 Uncertain:1
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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 586217). This variant is present in population databases (rs774128685, ExAC 0.002%). This sequence change replaces proline with leucine at codon 483 of the GRN protein (p.Pro483Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at