ENST00000327247.9:c.-69+231G>A

Variant names:

• chr1-155244275-C-T
• rs10908459
• ENST00000327247.9:c.-69+231G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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]

GBA1 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Gaucher disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• Gaucher disease perinatal lethal

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• late-onset Parkinson disease

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Gaucher disease type I

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Gaucher disease type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• Gaucher disease type III

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000327247.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	NM_001005741.3		c.-69+231G>A		intron	N/A	NP_001005741.1
	GBA1	NM_001005742.3		c.-50+231G>A		intron	N/A	NP_001005742.1
	GBA1	NM_001171811.2		c.-147+231G>A		intron	N/A	NP_001165282.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000327247.9	TSL:1	c.-69+231G>A		intron	N/A	ENSP00000314508.5
	GBA1	ENST00000428024.3	TSL:2	c.-147+231G>A		intron	N/A	ENSP00000397986.2
	GBA1	ENST00000467918.5	TSL:5	n.102-45G>A		intron	N/A

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.167 AC: 1 AN: 6

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.545 AC: 22486 AN: 41296

American (AMR) AF: 0.346 AC: 5280 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 948 AN: 3464

East Asian (EAS) AF: 0.702 AC: 3629 AN: 5166

South Asian (SAS) AF: 0.356 AC: 1709 AN: 4806

European-Finnish (FIN) AF: 0.315 AC: 3315 AN: 10514

Middle Eastern (MID) AF: 0.267 AC: 78 AN: 292

European-Non Finnish (NFE) AF: 0.290 AC: 19691 AN: 67920

Other (OTH) AF: 0.355 AC: 749 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.82
PhyloP100		0.16
PromoterAI		-0.035	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs10908459; hg19: chr1-155214066;