chr1-155236246-G-A
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_000157.4(GBA1):c.1223C>T(p.Thr408Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,613,292 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T408T) has been classified as Uncertain significance.
Frequency
Consequence
NM_000157.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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GBA1 | NM_000157.4 | c.1223C>T | p.Thr408Met | missense_variant, splice_region_variant | Exon 8 of 11 | ENST00000368373.8 | NP_000148.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00601 AC: 915AN: 152194Hom.: 5 Cov.: 32
GnomAD3 exomes AF: 0.00594 AC: 1491AN: 251106Hom.: 7 AF XY: 0.00583 AC XY: 792AN XY: 135750
GnomAD4 exome AF: 0.00708 AC: 10346AN: 1460980Hom.: 63 Cov.: 33 AF XY: 0.00695 AC XY: 5052AN XY: 726870
GnomAD4 genome AF: 0.00601 AC: 915AN: 152312Hom.: 5 Cov.: 32 AF XY: 0.00573 AC XY: 427AN XY: 74478
ClinVar
Submissions by phenotype
not provided Benign:8
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GBA1: BS2 -
This variant is associated with the following publications: (PMID: 32658388, 33281709, 32618053, 29487000, 28966932, 29842932, 30548430, 30146349, 30302829, 29396846, 28834018, 29140481, 27153395, 27648471, 28030538, 26000814, 27094865, 8774051, 22001711, 18987351, 22173904, 12694238) -
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not specified Benign:4
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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Variant summary: The GBA c.1223C>T (p.Thr408Met, also known as Thr369Met) variant located in the glycosyl hydrolase family 30, TIM-barrel domain (via InterPro) involves the alteration of a non-conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured due to low reliability index and p-value). This variant was found in 1708/277314 (7 homozygotes) control chromosomes (gnomAD and publication controls) at a frequency of 0.0061591, which is approximately 1 times the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005), suggesting this variant is likely a benign polymorphism. Multiple publications have cited the variant in affected individuals including a co-occurrence with another pathogenic GBA variant, D409H (also known as D448H - scored DV)(Hodanova_1999). Another publication, Walker_2003, cites the variant, T369M, as a polymorphism. A publication, Hodanova_2003, does indicate the variant could cause a functional impact but the authors state that at most would be a mild mutation even on the verge of a polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign. -
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Gaucher disease Uncertain:1Benign:1
The p.Thr408Met variant in GBA has been reported in at least 4 individuals with Gaucher disease (PMID: 12734541, 12694238, 10796875) and has been identified in 0.992% (249/25102) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs75548401). This variant has also been reported in ClinVar (VariationID: 93447) as a VUS by DST/NWU Preclinical Drug Development Platform, as likely benign by CeGaT Praxis fuer Humangnetik Tuebingen and Children's Mercy Hospital and Clinics, and as benign by PreventionGenetics, EGL Genetic Diagnostics, and Integrated Genetics. In vitro functional studies provide some evidence that the p.Thr408Met variant may not impact protein function (PMID: 12734541). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant was reported with a reported pathogenic variant in an unknown phase in 2 individuals with Gaucher disease (VariationID: 4290; PMID: 12734541, 10796875). However, this variant was also found in cis with other pathogenic variants, suggesting that it may not cause disease (VariationID: 65570, 4293; PMID: 12734541, 12694238). In summary, the clinical significance of the p.Thr408Met variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3, BP2, BS3_supporting (Richards 2015). -
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Gaucher disease perinatal lethal Uncertain:1Benign:1
This variant was classified as: Uncertain significance. The available evidence favors the benign nature of this variant, however the evidence is insufficent to prove its benign nature. The following ACMG criteria were applied in classifying this variant: BP4. -
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Parkinson disease, late-onset Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at