4-22735989-G-C

Variant names:

• chr4-22735989-G-C
• rs1239308424
• ENST00000508166.5:c.67G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000508166.5(GBA3):​c.67G>C​(p.Asp23His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D23N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA3 ENST00000508166.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.54
• Publications: 0 publications found

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]

LOC105374521 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38689107).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000508166.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA3	NR_102355.2		n.146G>C		non_coding_transcript_exon	Exon 2 of 5
	GBA3	NR_102356.2		n.146G>C		non_coding_transcript_exon	Exon 2 of 3
	GBA3	NR_102357.2		n.68G>C		non_coding_transcript_exon	Exon 2 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA3	ENST00000508166.5	TSL:1	c.67G>C	p.Asp23His	missense	Exon 2 of 5	ENSP00000427458.1
	GBA3	ENST00000503442.1	TSL:1	c.67G>C	p.Asp23His	missense	Exon 2 of 3	ENSP00000422220.1
	GBA3	ENST00000511446.2	TSL:2	c.-447G>C		5_prime_UTR	Exon 2 of 5	ENSP00000423754.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1460722 Hom.: 1 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726672

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111148

Other (OTH) AF: 0.0000331 AC: 2 AN: 60336

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.39	T
PhyloP100		2.5
PrimateAI	Uncertain	0.51	T
Vest4		0.47
MVP		0.51
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

Other links and lift over

dbSNP: rs1239308424; hg19: chr4-22737612;