Variant rs80356772 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The ENST00000368373.8(GBA1):c.1505G>T(p.Arg502Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R502C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 25)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GBA1
ENST00000368373.8 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.18

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 Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155235196-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.1505G>T	p.Arg502Leu	missense_variant, splice_region_variant	10/11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.1505G>T	p.Arg502Leu	missense_variant, splice_region_variant	10/11	1	NM_000157.4	ENSP00000357357	P1	P04062-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461212

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726906

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;D;.;.

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.082

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.95

.;D;D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.89

D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.9

L;L;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.5

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.050

T;T;T;T

Polyphen

0.12

B;B;.;.

Vest4

0.71

MutPred

0.62

Loss of catalytic residue at R502 (P = 0.0368);Loss of catalytic residue at R502 (P = 0.0368);.;.;

MVP

0.88

MPC

0.95

ClinPred

0.99

GERP RS

3.2

Varity_R

0.74

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.35

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.34

Position offset: -12

DS_DL_spliceai

0.35

Position offset: 0

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over