rs2230288

Variant names:

• chr1-155236376-C-T
• rs2230288
• NM_000157.4:c.1093G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-155236376-C-T
• chr1-155236376-C-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 3P and 11B. PM1 PP2 BP4_Moderate BP6 BS1 BS2

The NM_000157.4(GBA1):​c.1093G>A​(p.Glu365Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,614,092 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,risk factor (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E365G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 32)
  • Exomes 𝑓: 0.013 (173 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; risk factor criteria provided, conflicting classifications U:2 B:15 O:5
• Conservation: PhyloP100: 0.321
• Publications: 431 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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: 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: Benign. The variant received -8 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, 3 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=0.110501975).
• BP6: Variant 1-155236376-C-T is Benign according to our data. Variant chr1-155236376-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity|risk_factor. ClinVar VariationId is 199044.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1540/152250) while in subpopulation NFE AF = 0.0128 (868/67984). AF 95% confidence interval is 0.0121. There are 23 homozygotes in GnomAd4. There are 843 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AD,AR gene

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.1093G>A	p.Glu365Lys	missense	Exon 8 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.1093G>A	p.Glu365Lys	missense	Exon 9 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.1093G>A	p.Glu365Lys	missense	Exon 9 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.1093G>A	p.Glu365Lys	missense	Exon 8 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.1093G>A	p.Glu365Lys	missense	Exon 9 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.1159G>A	p.Glu387Lys	missense	Exon 10 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1541 AN: 152132 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0105 AC: 2630 AN: 251434 AF XY: 0.0102

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0438

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0125 AC: 18333 AN: 1461842 Hom.: 173 Cov.: 33 AF XY: 0.0121 AC XY: 8795 AN XY: 727234

African (AFR) AF: 0.00188 AC: 63 AN: 33476

American (AMR) AF: 0.00244 AC: 109 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00520 AC: 136 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00212 AC: 183 AN: 86258

European-Finnish (FIN) AF: 0.0435 AC: 2322 AN: 53406

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0134 AC: 14923 AN: 1111992

Other (OTH) AF: 0.00980 AC: 592 AN: 60394

GnomAD4 genome AF: 0.0101 AC: 1540 AN: 152250 Hom.: 23 Cov.: 32 AF XY: 0.0113 AC XY: 843 AN XY: 74442

African (AFR) AF: 0.00231 AC: 96 AN: 41564

American (AMR) AF: 0.00183 AC: 28 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.0482 AC: 511 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 868 AN: 67984

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0116 Hom.: 7

Bravo AF: 0.00634

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00980 AC: 1190

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00996

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; risk factor

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	7	not provided (8)
-	-	5	not specified (5)
-	-	2	Gaucher disease (3)
-	1	1	Gaucher disease perinatal lethal (2)
-	-	-	Hyperlipidemia;C0020538:Hypertensive disorder;C0242422:Parkinsonian disorder;C0497327:Dementia;C1836296:Lower limb muscle weakness;C3687424:Abnormal speech pattern (1)
-	-	-	Parkinson disease, late-onset (1)
-	-	-	Parkinsonian disorder (1)
-	-	-	Rigidity;C0040822:Tremor;C0151564:Cogwheel rigidity;C0242422:Parkinsonian disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	1.0	L
PhyloP100		0.32
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.59
Sift	Benign	0.78	T
Sift4G	Benign	0.87	T
Polyphen		0.015	B
Vest4		0.22
MPC		0.86
ClinPred		0.0093	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.84
Mutation Taster		=93/7	polymorphism

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: rs2230288; hg19: chr1-155206167;