rs121908300
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000157.4(GBA1):āc.751T>Cā(p.Tyr251His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 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 (ā ā ).
Frequency
Consequence
NM_000157.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GBA1 | NM_000157.4 | c.751T>C | p.Tyr251His | missense_variant | Exon 6 of 11 | ENST00000368373.8 | NP_000148.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461880Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727240
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Gaucher disease type I Pathogenic:1
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not provided Uncertain:1
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Gaucher disease Uncertain:1
The p.Tyr251His variant in GBA has been reported in 3 individuals with Gaucher disease (PMID: 8432537, 24685312) and has been identified in 0.010% (1/10080) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908300). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. 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 presence of this variant in combination with a reported pathogenic variant in 3 individuals with Gaucher disease increases the likelihood that the p.Tyr251His variant is pathogenic (VariationID: 4290; PMID: 8432537, 24685312). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3, PP3 (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at