chr4-22736145-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The ENST00000508166.5(GBA3):c.223C>T(p.Arg75Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000051 ( 0 hom. )
Consequence
GBA3
ENST00000508166.5 missense
ENST00000508166.5 missense
Scores
3
4
1
Clinical Significance
Conservation
PhyloP100: 3.18
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 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.38523576).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GBA3 | NR_102355.2 | n.302C>T | non_coding_transcript_exon_variant | 2/5 | |||
LOC105374521 | XR_007058431.1 | n.860-2453G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GBA3 | ENST00000508166.5 | c.223C>T | p.Arg75Cys | missense_variant | 2/5 | 1 | P5 | ||
GBA3 | ENST00000503442.1 | c.223C>T | p.Arg75Cys | missense_variant | 2/3 | 1 | A2 | ||
GBA3 | ENST00000511446.2 | c.-291C>T | 5_prime_UTR_variant | 2/5 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152102Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000603 AC: 15AN: 248816Hom.: 0 AF XY: 0.0000593 AC XY: 8AN XY: 135016
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GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461438Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36AN XY: 727006
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GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74306
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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 | Aug 02, 2021 | The c.223C>T (p.R75C) alteration is located in exon 2 (coding exon 2) of the GBA3 gene. This alteration results from a C to T substitution at nucleotide position 223, causing the arginine (R) at amino acid position 75 to be replaced by a cysteine (C). 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
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D;.
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
MetaRNN
Benign
T;T
PrimateAI
Uncertain
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