rs368060

Variant names:

• chr1-155235217-C-G
• rs368060
• NM_000157.4:c.1483G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000157.4(GBA1):​c.1483G>C​(p.Ala495Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000581 in 1,612,176 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A495G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 25)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:1
• Conservation: PhyloP100: 1.14
• Publications: 61 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: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000157.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.

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.1483G>C	p.Ala495Pro	missense	Exon 10 of 11	NP_000148.2
	GBA1	NM_001005741.3		c.1483G>C	p.Ala495Pro	missense	Exon 11 of 12	NP_001005741.1
	GBA1	NM_001005742.3		c.1483G>C	p.Ala495Pro	missense	Exon 11 of 12	NP_001005742.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.1483G>C	p.Ala495Pro	missense	Exon 10 of 11	ENSP00000357357.3
	GBA1	ENST00000327247.9	TSL:1	c.1483G>C	p.Ala495Pro	missense	Exon 11 of 12	ENSP00000314508.5
	GBA1	ENST00000427500.7	TSL:2	c.1336G>C	p.Ala446Pro	missense	Exon 9 of 10	ENSP00000402577.2

Frequencies

GnomAD3 genomes AF: 0.000787 AC: 119 AN: 151116 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.000948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00285

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000980

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0000948

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000340

Gnomad OTH AF: 0.00146

GnomAD2 exomes AF: 0.000139 AC: 35 AN: 251138 AF XY: 0.000118

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000556 AC: 813 AN: 1460942 Hom.: 0 Cov.: 31 AF XY: 0.000581 AC XY: 422 AN XY: 726720

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000867 AC: 29 AN: 33460

American (AMR) AF: 0.00114 AC: 51 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00174 AC: 69 AN: 39634

South Asian (SAS) AF: 0.00124 AC: 107 AN: 86052

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000462 AC: 513 AN: 1111470

Other (OTH) AF: 0.000646 AC: 39 AN: 60348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000813 AC: 123 AN: 151234 Hom.: 1 Cov.: 25 AF XY: 0.000812 AC XY: 60 AN XY: 73894

African (AFR) AF: 0.000921 AC: 38 AN: 41252

American (AMR) AF: 0.00317 AC: 48 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.000983 AC: 5 AN: 5088

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4758

European-Finnish (FIN) AF: 0.0000948 AC: 1 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000340 AC: 23 AN: 67718

Other (OTH) AF: 0.00144 AC: 3 AN: 2080

Alfa AF: 0.000869 Hom.: 0

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	1	not specified (3)
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.38
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.85	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.67
Sift	Benign	0.20	T
Sift4G	Benign	0.33	T
Polyphen		0.037	B
Vest4		0.58
MVP		0.93
MPC		1.6
ClinPred		0.013	T
GERP RS		2.2
Varity_R		0.68
gMVP		0.95
Mutation Taster		=10/90	disease causing

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: rs368060; hg19: chr1-155205008; COSMIC: COSV105891350;