Variant rs121908307 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_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 (★★). Synonymous variant affecting the same amino acid position (i.e. S403S) has been classified as Likely benign.

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

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

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

PM2

Very rare variant in population databases, with high coverage;

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 id 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	P04062-1A0A068F658

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		P04062-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251292

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135840

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

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

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1990	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2022

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

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;.;.

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

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