4-22747811-G-C

Variant names:

• chr4-22747811-G-C
• rs1716821842
• ENST00000508166.5:c.802G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000508166.5(GBA3):​c.802G>C​(p.Val268Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 7/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GBA3 ENST00000508166.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19367349).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA3	NR_102355.2	n.881G>C		non_coding_transcript_exon_variant	Exon 3 of 5
GBA3	NR_102357.2	n.803G>C		non_coding_transcript_exon_variant	Exon 3 of 5
GBA3	NR_102356.2	n.365+11603G>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA3	ENST00000508166.5	c.802G>C	p.Val268Leu	missense_variant	Exon 3 of 5	1		ENSP00000427458.1
GBA3	ENST00000503442.1	c.286+11603G>C		intron_variant	Intron 2 of 2	1		ENSP00000422220.1
GBA3	ENST00000511446.2	c.289G>C	p.Val97Leu	missense_variant	Exon 3 of 5	2		ENSP00000423754.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461674 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727114

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.802G>C (p.V268L) alteration is located in exon 3 (coding exon 3) of the GBA3 gene. This alteration results from a G to C substitution at nucleotide position 802, causing the valine (V) at amino acid position 268 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.19	T
PrimateAI	Benign	0.47	T
Vest4		0.086
MVP		0.49
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1716821842; hg19: chr4-22749434;