1-155235878-G-T

Variant names:

• chr1-155235878-G-T
• rs3115534
• NM_000157.4:c.1225-34C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000157.4(GBA1):​c.1225-34C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 151,042 control chromosomes in the GnomAD database, including 68,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68998 hom., cov: 32)
  • Exomes 𝑓: 0.83 (459479 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.116
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 1-155235878-G-T is Benign according to our data. Variant chr1-155235878-G-T is described in ClinVar as Benign. ClinVar VariationId is 256871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000157.4. 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_000157.4	MANE Select	c.1225-34C>A		intron	N/A	NP_000148.2
	GBA1	NM_001005741.3		c.1225-34C>A		intron	N/A	NP_001005741.1
	GBA1	NM_001005742.3		c.1225-34C>A		intron	N/A	NP_001005742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.1225-34C>A		intron	N/A	ENSP00000357357.3
	GBA1	ENST00000327247.9	TSL:1	c.1225-34C>A		intron	N/A	ENSP00000314508.5
	GBA1	ENST00000948997.1		c.1291-34C>A		intron	N/A	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.953 AC: 143845 AN: 150920 Hom.: 68942 Cov.: 32

Gnomad AFR AF: 0.841

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.983

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.998

Gnomad MID AF: 0.977

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.970

GnomAD2 exomes AF: 0.987 AC: 247043 AN: 250388 AF XY: 0.990

Gnomad AFR exome AF: 0.840

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.995

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.992

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.832 AC: 1150840 AN: 1383774 Hom.: 459479 Cov.: 49 AF XY: 0.835 AC XY: 576141 AN XY: 690088

African (AFR) AF: 0.775 AC: 25370 AN: 32752

American (AMR) AF: 0.928 AC: 40931 AN: 44124

Ashkenazi Jewish (ASJ) AF: 0.856 AC: 21836 AN: 25504

East Asian (EAS) AF: 0.978 AC: 38342 AN: 39214

South Asian (SAS) AF: 0.886 AC: 74253 AN: 83784

European-Finnish (FIN) AF: 0.970 AC: 50994 AN: 52576

Middle Eastern (MID) AF: 0.873 AC: 4898 AN: 5612

European-Non Finnish (NFE) AF: 0.810 AC: 844868 AN: 1042460

Other (OTH) AF: 0.855 AC: 49348 AN: 57748

GnomAD4 genome AF: 0.953 AC: 143962 AN: 151042 Hom.: 68998 Cov.: 32 AF XY: 0.955 AC XY: 70514 AN XY: 73830

African (AFR) AF: 0.841 AC: 34845 AN: 41432

American (AMR) AF: 0.983 AC: 14910 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3438 AN: 3442

East Asian (EAS) AF: 1.00 AC: 5164 AN: 5166

South Asian (SAS) AF: 0.999 AC: 4793 AN: 4800

European-Finnish (FIN) AF: 0.998 AC: 10460 AN: 10476

Middle Eastern (MID) AF: 0.975 AC: 273 AN: 280

European-Non Finnish (NFE) AF: 0.998 AC: 67157 AN: 67290

Other (OTH) AF: 0.970 AC: 2028 AN: 2090

Alfa AF: 0.978 Hom.: 13002

Bravo AF: 0.949

Asia WGS AF: 0.989 AC: 3441 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Gaucher disease (1)
-	-	1	Gaucher disease perinatal lethal (1)
-	-	1	Gaucher disease type I (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.7
DANN	Benign	0.84
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs3115534; hg19: chr1-155205669;