rs77829017
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000157.4(GBA1):c.254G>A(p.Gly85Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,876 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
GBA1
NM_000157.4 missense
NM_000157.4 missense
Scores
12
6
1
Clinical Significance
Conservation
PhyloP100: 6.45
Genes affected
GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 1-155239939-C-T is Pathogenic according to our data. Variant chr1-155239939-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 4296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GBA1 | NM_000157.4 | c.254G>A | p.Gly85Glu | missense_variant | 3/11 | ENST00000368373.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GBA1 | ENST00000368373.8 | c.254G>A | p.Gly85Glu | missense_variant | 3/11 | 1 | NM_000157.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
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31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251318Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135840
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461876Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727236
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GnomAD4 genome Cov.: 31
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31
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Gaucher disease Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2017 | Variant summary: The GBA c.254G>A (p.Gly85Glu) variant involves the alteration of a conserved nucleotide, resulting in a missense change. 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1/246122 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005). The variant has been identified in numerous patients diagnosed with Gaucher disease Type 1, as a homozygous and compound heterozygous allele, and is a common Gaucher disease allele in East Asian populations (Jeong_2011). One study reported the GBA enzyme activity levels in compound heterozygous patients to be ~10-20% of normal levels (Choi_2015). In addition, multiple reputable databases/clinical diagnostic laboratory have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 15, 2020 | The p.Gly85Glu variant in GBA has been reported in at least 15 Korean individuals with Gaucher disease (PMID: 22375149, 20729108, 30764785) and has been identified in 0.003% (1/30614) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs77829017). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 4296) as pathogenic by OMIM. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Gaucher disease based on low glucocerebrosidase activity consistent with disease (PMID: 22375149, 30764785). The presence of this variant in 2 affected homozygotes and in combination with reported pathogenic variants in 9 individuals with Gaucher disease increases the likelihood that the p.Gly85Glu variant is pathogenic (VariationID: 4288, 4301, 65570, 4328, 4297; PMID: 22375149, 20729108, 30764785). In summary, this variant meets criteria to be classified as pathogenic for Gaucher disease in an autosomal recessive manner based on the presence of the variant in affected homozygotes and compound heterozygotes in combination with pathogenic variants and the phenotype of patients with the variant being highly specific for Gaucher disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4 (Richards 2015). - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Gaucher disease type I Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1996 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 29, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G46E); This variant is associated with the following publications: (PMID: 32658388, 37530313, 29869463, 22375149, 30764785, 20729108, 33176831, 24904648, 8829654, 33301762) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;D;.
Vest4
MutPred
Loss of methylation at R86 (P = 0.0438);Loss of methylation at R86 (P = 0.0438);Loss of methylation at R86 (P = 0.0438);
MVP
MPC
0.20
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at