rs141111290
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting
The NM_002087.4(GRN):c.1555G>A(p.Val519Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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 Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GRN | ENST00000053867.8 | c.1555G>A | p.Val519Met | missense_variant | Exon 12 of 13 | 1 | NM_002087.4 | ENSP00000053867.2 | ||
GRN | ENST00000589265.5 | c.1084G>A | p.Val362Met | missense_variant | Exon 8 of 9 | 5 | ENSP00000467616.1 | |||
GRN | ENST00000586443.1 | c.994G>A | p.Val332Met | missense_variant | Exon 7 of 7 | 3 | ENSP00000465673.1 | |||
GRN | ENST00000586242.1 | c.187G>A | p.Val63Met | missense_variant | Exon 2 of 3 | 3 | ENSP00000467837.1 |
Frequencies
GnomAD3 genomes AF: 0.000394 AC: 60AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251372Hom.: 1 AF XY: 0.000132 AC XY: 18AN XY: 135872
GnomAD4 exome AF: 0.0000588 AC: 86AN: 1461742Hom.: 0 Cov.: 34 AF XY: 0.0000495 AC XY: 36AN XY: 727164
GnomAD4 genome AF: 0.000394 AC: 60AN: 152278Hom.: 0 Cov.: 33 AF XY: 0.000363 AC XY: 27AN XY: 74466
ClinVar
Submissions by phenotype
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions;C3539123:Neuronal ceroid lipofuscinosis 11 Uncertain:2
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This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 519 of the GRN protein (p.Val519Met). This variant is present in population databases (rs141111290, gnomAD 0.04%). This missense change has been observed in individual(s) with blindness or dementia (PMID: 22312439, 25333068, 29486463, 32483926). ClinVar contains an entry for this variant (Variation ID: 588635). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GRN protein function with a positive predictive value of 80%. 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. -
Inborn genetic diseases Uncertain:1
The c.1555G>A (p.V519M) alteration is located in exon 12 (coding exon 11) of the GRN gene. This alteration results from a G to A substitution at nucleotide position 1555, causing the valine (V) at amino acid position 519 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.01% (26/251372) total alleles studied. The highest observed frequency was 0.046% (16/34582) of Latino alleles. This variant has been detected in cohorts of individuals with Alzheimer's disease and frontotemporal lobar degeneration; however, specific clinical information was not provided for the affected individuals (Cruchaga, 2012; Lee, 2014). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Has been observed in individuals with dementia and reported as possibly related; however, this variant was also observed in unaffected control samples (Cruchaga et al., 2012; Blue et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25333068, 28527211, 29486463, 22312439, 32483926) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at