chr4-22747593-A-C
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The ENST00000508166.5(GBA3):c.584A>C(p.His195Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,896 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 (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
GBA3
ENST00000508166.5 missense
ENST00000508166.5 missense
Scores
4
1
2
Clinical Significance
Conservation
PhyloP100: 6.11
Genes affected
GBA3 (HGNC:19069): (glucosylceramidase beta 3 (gene/pseudogene)) The protein encoded by this gene is a cytosolic enzyme that can hydrolyze several types of glycosides. The enzyme has its highest activity at neutral pH and is predominantly expressed in human liver, kidney, intestine, and spleen. This gene is a polymorphic pseudogene, with the most common allele being the functional allele that encodes the full-length protein. Some individuals contain a single nucleotide polymorphism that results in a premature stop codon in the coding region, and therefore this allele is pseudogenic due to the failure to produce a functional full-length protein. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.869
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GBA3 | NR_102355.2 | n.663A>C | non_coding_transcript_exon_variant | 3/5 | |||
GBA3 | NR_102357.2 | n.585A>C | non_coding_transcript_exon_variant | 3/5 | |||
GBA3 | NR_102356.2 | n.365+11385A>C | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GBA3 | ENST00000508166.5 | c.584A>C | p.His195Pro | missense_variant | 3/5 | 1 | P5 | ||
GBA3 | ENST00000503442.1 | c.286+11385A>C | intron_variant | 1 | A2 | ||||
GBA3 | ENST00000511446.2 | c.71A>C | p.His24Pro | missense_variant | 3/5 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 249046Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135108
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461692Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727122
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 22, 2023 | The c.584A>C (p.H195P) alteration is located in exon 3 (coding exon 3) of the GBA3 gene. This alteration results from a A to C substitution at nucleotide position 584, causing the histidine (H) at amino acid position 195 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
MetaRNN
Pathogenic
D
PrimateAI
Benign
T
Vest4
MVP
GERP RS
Splicing
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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