rs77284004
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Moderate
The NM_000157.4(GBA1):c.1256A>C(p.Asp419Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,892 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 Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D419N) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000157.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GBA1 | NM_000157.4 | c.1256A>C | p.Asp419Ala | missense_variant | Exon 9 of 11 | ENST00000368373.8 | NP_000148.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727246
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Gaucher disease Pathogenic:1
Variant summary: GBA1 c.1256A>C (p.Asp419Ala) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5e-06 in 1614186 control chromosomes. c.1256A>C has been reported in the literature in the compound heterozygous state in individuals affected with Gaucher Disease (Walley_1993, Saville_2020, Mao_2001, DAmore_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34649574, 11243731, 31707742, 8268935). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at