rs368060

Positions:

chr1-155235217-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

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).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 25)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:1

Conservation

PhyloP100: 1.14

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000157.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.1483G>C	p.Ala495Pro	missense_variant	10/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.1483G>C	p.Ala495Pro	missense_variant	10/11	1	NM_000157.4	P1	P04062-1

Frequencies

GnomAD3 genomes

AF:

0.000787

AC:

119

AN:

151116

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000139

AC:

AN:

251138

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135730

show subpopulations

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 SAS exome

AF:

0.00

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.:

Cov.:

AF XY:

0.000581

AC XY:

422

AN XY:

726720

show subpopulations

Gnomad4 AFR exome

AF:

0.000867

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00174

Gnomad4 SAS exome

AF:

0.00124

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000462

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000813

AC:

123

AN:

151234

Hom.:

Cov.:

AF XY:

0.000812

AC XY:

AN XY:

73894

show subpopulations

Gnomad4 AFR

AF:

0.000921

Gnomad4 AMR

AF:

0.00317

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000983

Gnomad4 SAS

AF:

0.00105

Gnomad4 FIN

AF:

0.0000948

Gnomad4 NFE

AF:

0.000340

Gnomad4 OTH

AF:

0.00144

Alfa

AF:

0.000869

Hom.:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Pathogenic:1Uncertain:1Benign:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2017	The p.[L483P;A495P;V499V] pathogenic mutation (also known as c.[1448T>C;1483G>C;1497G>C]), located in coding exon 10 of the GBA gene, results from a T to C substitution at nucleotide position 1448, a G to C substitution at nucleotide position 1483, and a G to C substitution at nucleotide position 1497. This complex allele, also referred to as recNciI and L444P;A456P;V460V, has been reported in multiple cases of Gaucher disease, either in homozygous state or in trans with another GBA pathogenic mutation. It has been suggested that the complex allele results from gene recombination between GBA and its pseudogene (Zimran A et al. J. Clin. Invest., 1990 Jan;85:219-22; Latham T et al. Am. J. Hum. Genet., 1990 Jul;47:79-86; Horowitz M et al. Am. J. Hum. Genet., 1993 Oct;53:921-30; Strasberg PM et al. Biochem. Med. Metab. Biol., 1994 Oct;53:16-21; Sidransky E et al. J. Med. Genet., 1996 Feb;33:132-6; Tayebi N et al. Am. J. Hum. Genet., 2003 Mar;72:519-34; Saranjam H et al. Eur. J. Hum. Genet., 2013 Jan;21:115-7). In addition, functional studies showed that the complex allele greatly reduces enzyme activity (Grace ME et al. J. Biol. Chem., 1994 Jan;269:2283-91; Pasmanik-Chor M et al. Hum. Mol. Genet., 1997 Jun;6:887-95). Based on the supporting evidence, this complex allele is interpreted as a disease-causing mutation. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2024	Variant summary: GBA1 c.1483G>C (p.Ala495Pro) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 1612176 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in GBA1 causing Gaucher Disease (0.00058 vs 0.005), allowing no conclusion about variant significance. c.1483G>C has been reported in the literature as part of the frequently encountered GBA complex alleles, RecTL or Rec NciI in individuals affected with Gaucher Disease and GBA-associated phenotypes of Parkinson Disease (example, Latham_1990, Grace_1994, Zimran_1994, Lau_1999, Stone_2000, Wittman_2012, Jesus_2016, Bhutada_2018, Kang_2018, Marchi_2020, Petrucci_2020). Rec TL and Rec NCiI are complex recombination alleles that carry two or more disease causing mutations due to gene conversion events between the GBA and the pseudo-GBA (GBAP) genes. To our knowledge, this variant has never been reported in isolation as a homozygous or compound heterozygous genotype in individuals with Gaugher Disease. These report(s) do not provide unequivocal conclusions about association of the variant with Gaucher Disease. At least one publication reports in-vitro experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Grace_1994). The following publications have been ascertained in the context of this evaluation (PMID: 29854527, 8294487, 28030538, 29934114, 2349952, 10369158, 32031266, 32658388, 38647370, 10685993, 23430949, 8160756). ClinVar contains an entry for this variant (Variation ID: 93450). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Benign, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2012	- -

not provided

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	GBA1: PM2, PM3, PP1, PP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 29, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.85

D;D;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.59

.;T;T;T

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.59

D;D;D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.3

M;M;.;.

MutationTaster

Benign

0.96

A;A;A;A;A

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

N;N;N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.33

T;T;T;T

Polyphen

0.037

B;B;.;.

Vest4

0.58

MVP

0.93

MPC

1.6

ClinPred

0.013

GERP RS

2.2

Varity_R

0.68

gMVP

0.95

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over