rs10908459

Positions:

• chr1-155244275-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000327247.9(GBA1):​c.-69+231G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.382 in 151,736 control chromosomes in the GnomAD database, including 12,244 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.38 (12244 hom., cov: 31)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: GBA1 ENST00000327247.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.159

Genes affected

GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.683 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_001005741.3	c.-69+231G>A		intron_variant			NP_001005741.1
GBA1	NM_001005742.3	c.-50+231G>A		intron_variant			NP_001005742.1
GBA1	NM_001171811.2	c.-147+231G>A		intron_variant			NP_001165282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000327247.9	c.-69+231G>A		intron_variant		1		ENSP00000314508	P1
GBA1	ENST00000428024.3	c.-147+231G>A		intron_variant		2		ENSP00000397986
GBA1	ENST00000467918.5	n.102-45G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57926 AN: 151612 Hom.: 12209 Cov.: 31

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.357

GnomAD4 exome AF: 0.167 AC: 1 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 NFE exome AF: 0.167

GnomAD4 genome AF: 0.382 AC: 58008 AN: 151730 Hom.: 12244 Cov.: 31 AF XY: 0.382 AC XY: 28335 AN XY: 74152

Gnomad4 AFR AF: 0.545

Gnomad4 AMR AF: 0.346

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.702

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.315

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.355

Alfa AF: 0.332 Hom.: 1169

Bravo AF: 0.396

Asia WGS AF: 0.549 AC: 1907 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.82

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10908459; hg19: chr1-155214066;