chr1-155235217-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000157.4(GBA1):āc.1483G>Cā(p.Ala495Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,612,176 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000157.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GBA1 | NM_000157.4 | c.1483G>C | p.Ala495Pro | missense_variant | Exon 10 of 11 | ENST00000368373.8 | NP_000148.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000787 AC: 119AN: 151116Hom.: 1 Cov.: 25
GnomAD3 exomes AF: 0.000139 AC: 35AN: 251138Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135730
GnomAD4 exome AF: 0.000556 AC: 813AN: 1460942Hom.: 0 Cov.: 31 AF XY: 0.000581 AC XY: 422AN XY: 726720
GnomAD4 genome AF: 0.000813 AC: 123AN: 151234Hom.: 1 Cov.: 25 AF XY: 0.000812 AC XY: 60AN XY: 73894
ClinVar
Submissions by phenotype
not specified Pathogenic:1Uncertain:1Benign:1
Variant summary: GBA1 c.1483G>C (p.Ala495Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 1612176 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GBA1 causing Gaucher Disease (0.00058 vs 0.005), allowing no conclusion about variant significance. c.1483G>C has been reported in the literature as part of the frequently encountered GBA complex alleles, RecTL or Rec NciI in individuals affected with Gaucher Disease and GBA-associated phenotypes of Parkinson Disease (example, Latham_1990, Grace_1994, Zimran_1994, Lau_1999, Stone_2000, Wittman_2012, Jesus_2016, Bhutada_2018, Kang_2018, Marchi_2020, Petrucci_2020). Rec TL and Rec NCiI are complex recombination alleles that carry two or more disease causing mutations due to gene conversion events between the GBA and the pseudo-GBA (GBAP) genes. To our knowledge, this variant has never been reported in isolation as a homozygous or compound heterozygous genotype in individuals with Gaugher Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Gaucher Disease. At least one publication reports in-vitro experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Grace_1994). The following publications have been ascertained in the context of this evaluation (PMID: 29854527, 8294487, 28030538, 29934114, 2349952, 10369158, 32031266, 32658388, 38647370, 10685993, 23430949, 8160756). ClinVar contains an entry for this variant (Variation ID: 93450). Based on the evidence outlined above, the variant was classified as uncertain significance. -
The p.[L483P;A495P;V499V] pathogenic mutation (also known as c.[1448T>C;1483G>C;1497G>C]), located in coding exon 10 of the GBA gene, results from a T to C substitution at nucleotide position 1448, a G to C substitution at nucleotide position 1483, and a G to C substitution at nucleotide position 1497. This complex allele, also referred to as recNciI and L444P;A456P;V460V, has been reported in multiple cases of Gaucher disease, either in homozygous state or in trans with another GBA pathogenic mutation. It has been suggested that the complex allele results from gene recombination between GBA and its pseudogene (Zimran A et al. J. Clin. Invest., 1990 Jan;85:219-22; Latham T et al. Am. J. Hum. Genet., 1990 Jul;47:79-86; Horowitz M et al. Am. J. Hum. Genet., 1993 Oct;53:921-30; Strasberg PM et al. Biochem. Med. Metab. Biol., 1994 Oct;53:16-21; Sidransky E et al. J. Med. Genet., 1996 Feb;33:132-6; Tayebi N et al. Am. J. Hum. Genet., 2003 Mar;72:519-34; Saranjam H et al. Eur. J. Hum. Genet., 2013 Jan;21:115-7). In addition, functional studies showed that the complex allele greatly reduces enzyme activity (Grace ME et al. J. Biol. Chem., 1994 Jan;269:2283-91; Pasmanik-Chor M et al. Hum. Mol. Genet., 1997 Jun;6:887-95). Based on the supporting evidence, this complex allele is interpreted as a disease-causing mutation. -
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not provided Pathogenic:1Uncertain:1
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GBA1: PM2, PM3, PP1, PP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at