chr1-155235020-T-C

Variant names:

• chr1-155235020-T-C
• rs1571964031
• NM_000157.4:c.1586A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BP4

The NM_000157.4(GBA1):​c.1586A>G​(p.His529Arg) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0000025 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94
• Publications: 0 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: Genomics England PanelApp, Laboratory for Molecular Medicine, G2P
• 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), Orphanet, Genomics England PanelApp
• Gaucher disease type II

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• 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 2 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, 5 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34169942).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	NM_000157.4	MANE Select	c.1586A>G	p.His529Arg	missense	Exon 11 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.1586A>G	p.His529Arg	missense	Exon 12 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.1586A>G	p.His529Arg	missense	Exon 12 of 12	NP_001005742.1	P04062-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	ENST00000368373.8	TSL:1 MANE Select	c.1586A>G	p.His529Arg	missense	Exon 11 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.1586A>G	p.His529Arg	missense	Exon 12 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.1652A>G	p.His551Arg	missense	Exon 13 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000255 AC: 2 AN: 785818 Hom.: 0 Cov.: 11 AF XY: 0.00000495 AC XY: 2 AN XY: 403748

African (AFR) AF: 0.00 AC: 0 AN: 19950

American (AMR) AF: 0.00 AC: 0 AN: 34066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20116

East Asian (EAS) AF: 0.00 AC: 0 AN: 32628

South Asian (SAS) AF: 0.00 AC: 0 AN: 64356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46082

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2908

European-Non Finnish (NFE) AF: 0.00000379 AC: 2 AN: 528196

Other (OTH) AF: 0.00 AC: 0 AN: 37516

GnomAD4 genome Cov.: 12

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Parkinson disease, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.59	N
REVEL	Pathogenic	0.66
Sift	Benign	0.41	T
Sift4G	Benign	0.63	T
Polyphen		0.65	P
Vest4		0.38
MutPred		0.64		Gain of MoRF binding (P = 0.0161)
MVP		0.93
MPC		1.1
ClinPred		0.37	T
GERP RS		3.2
Varity_R		0.55
gMVP		0.90
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1571964031; hg19: chr1-155204811;