rs121908307

Positions:

• chr1-155236261-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.32

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]

ACMG classification

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/exons	MANE	UniProt
GBA1	NM_000157.4	c.1208G>C	p.Ser403Thr	missense_variant	8/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1208G>C	p.Ser403Thr	missense_variant	8/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251292 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135840

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: 1 AN: 1461618 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727154

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.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease type I Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1990	- -
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). -

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	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.88	D;D;.;.
Eigen	Benign	-0.054
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.6	L;L;.;.
MutationTaster	Benign	0.15	A;A;A;A;A
PrimateAI	Uncertain	0.59	T
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	D
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

Other links and lift over

dbSNP: rs121908307; hg19: chr1-155206052;