rs121908307

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000157.4(GBA1):c.1208G>C(p.Ser403Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S403G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 5.32

Publications

5 publications found

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 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

GBA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000157.4

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 1-155236261-C-G is Pathogenic according to our data. Variant chr1-155236261-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4 link	c.1208G>C	p.Ser403Thr	missense_variant	Exon 8 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 link	c.1208G>C	p.Ser403Thr	missense_variant	Exon 8 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251292

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461618

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111786

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gaucher disease type I

Pathogenic:2

Jul 01, 1990

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Ser403Thr variant in GBA has been reported in 4 individuals with Gaucher disease (PMID: 1899336, 26756743, 18586596) and has been identified in 0.001% (1/113654) of European (non-Finnish) chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908307). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. A likely pathogenic variant, resulting in a different amino acid change at the same position, p.Ser403Arg, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 16039881, 14757438, 11783951, 21384230, 22429443). Additionally, the presence of this variant in combination with a reported pathogenic variant and in 4 individuals with Gaucher disease increases the likelihood that the p.Ser403Thr variant is pathogenic (VariationID: 4288, PMID: 1899336, 26756743, 18586596). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM2, PM5_supporting (Richards 2015). -

not provided

Pathogenic:1

Mar 02, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect with reduced enzyme activity compared to wildtype (Grace et al., 1994; Liou et al., 2006); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as S364T; This variant is associated with the following publications: (PMID: 16293621, 8294487, 21228398, 26756743, 18586596, 1899336) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Pathogenic

0.88

D;D;.;.

Eigen

Benign

-0.054

Eigen_PC

Benign

0.052

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.71

.;T;T;T

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.6

L;L;.;.

PhyloP100

5.3

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.4

N;N;N;N

REVEL

Pathogenic

0.66

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.27

T;T;T;T

Polyphen

0.43

B;B;.;.

Vest4

0.81

MutPred

0.70

Loss of disorder (P = 0.0742);Loss of disorder (P = 0.0742);.;.;

MVP

0.89

MPC

0.79

ClinPred

0.54

GERP RS

3.6

Varity_R

0.55

gMVP

0.98

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over