rs150466109

Variant names:

• chr1-155240707-T-C
• rs150466109
• NM_000157.4:c.38A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-155240707-T-C
• chr1-155240707-T-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000157.4(GBA1):​c.38A>G​(p.Lys13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 1,613,436 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (118 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (104 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: -0.211
• 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: 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 -19 ACMG points.

• 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=0.0018802583).
• BP6: Variant 1-155240707-T-C is Benign according to our data. Variant chr1-155240707-T-C is described in ClinVar as Benign. ClinVar VariationId is 196296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0746 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBA1	NM_000157.4	MANE Select	c.38A>G	p.Lys13Arg	missense	Exon 2 of 11	NP_000148.2	P04062-1
	GBA1	NM_001005741.3		c.38A>G	p.Lys13Arg	missense	Exon 3 of 12	NP_001005741.1	P04062-1
	GBA1	NM_001005742.3		c.38A>G	p.Lys13Arg	missense	Exon 3 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.38A>G	p.Lys13Arg	missense	Exon 2 of 11	ENSP00000357357.3	P04062-1
	GBA1	ENST00000327247.9	TSL:1	c.38A>G	p.Lys13Arg	missense	Exon 3 of 12	ENSP00000314508.5	P04062-1
	GBA1	ENST00000948997.1		c.38A>G	p.Lys13Arg	missense	Exon 3 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3374 AN: 152110 Hom.: 117 Cov.: 32

Gnomad AFR AF: 0.0769

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00565 AC: 1418 AN: 250914 AF XY: 0.00395

Gnomad AFR exome AF: 0.0763

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00230 AC: 3354 AN: 1461208 Hom.: 104 Cov.: 31 AF XY: 0.00191 AC XY: 1385 AN XY: 726942

African (AFR) AF: 0.0784 AC: 2622 AN: 33444

American (AMR) AF: 0.00412 AC: 184 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53172

Middle Eastern (MID) AF: 0.00625 AC: 36 AN: 5762

European-Non Finnish (NFE) AF: 0.000138 AC: 153 AN: 1111674

Other (OTH) AF: 0.00545 AC: 329 AN: 60362

GnomAD4 genome AF: 0.0222 AC: 3382 AN: 152228 Hom.: 118 Cov.: 32 AF XY: 0.0204 AC XY: 1517 AN XY: 74418

African (AFR) AF: 0.0769 AC: 3191 AN: 41514

American (AMR) AF: 0.00811 AC: 124 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68024

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0139 Hom.: 64

Bravo AF: 0.0253

ESP6500AA AF: 0.0708 AC: 312

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00705 AC: 856

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Gaucher disease (1)
1	-	-	Gaucher disease type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	4.8
DANN	Benign	0.66
DEOGEN2	Benign	0.34	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0019	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	0.20	N
PhyloP100		-0.21
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.18
Sift	Benign	0.39	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.69
MPC		0.022
ClinPred		0.0030	T
GERP RS		-0.40
Varity_R		0.029
gMVP		0.28
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs150466109; hg19: chr1-155210498; COSMIC: COSV106098715; COSMIC: COSV106098715;