Genetic Variant GBA1:p.Arg535His (chr1-155235002-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 13P and 1B. PM1PM5PP2PP5_Very_StrongBP4

The NM_000157.4(GBA1):c.1604G>A(p.Arg535His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign 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. R535C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000055 ( 0 hom., cov: 11)

Exomes 𝑓: 0.00012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19O:1

Conservation

PhyloP100: 0.830

Publications

60 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: Genomics England PanelApp, Laboratory for Molecular Medicine, G2P
late-onset Parkinson disease
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
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: Genomics England PanelApp, Orphanet
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 12 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-155235003-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 242383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

PP5

Variant 1-155235002-C-T is Pathogenic according to our data. Variant chr1-155235002-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.32971787). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000157.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBA1	NM_000157.4	MANE Select	c.1604G>A	p.Arg535His	missense	Exon 11 of 11	NP_000148.2	P04062-1
GBA1	NM_001005741.3		c.1604G>A	p.Arg535His	missense	Exon 12 of 12	NP_001005741.1	P04062-1
GBA1	NM_001005742.3		c.1604G>A	p.Arg535His	missense	Exon 12 of 12	NP_001005742.1	P04062-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GBA1	ENST00000368373.8	TSL:1 MANE Select	c.1604G>A	p.Arg535His	missense	Exon 11 of 11	ENSP00000357357.3	P04062-1
GBA1	ENST00000327247.9	TSL:1	c.1604G>A	p.Arg535His	missense	Exon 12 of 12	ENSP00000314508.5	P04062-1
GBA1	ENST00000948997.1		c.1670G>A	p.Arg557His	missense	Exon 13 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes

AF:

0.0000553

AC:

AN:

90450

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00123

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000223

Gnomad OTH

AF:

0.000931

GnomAD2 exomes

AF:

0.000182

AC:

AN:

170078

AF XY:

0.000155

show subpopulations

Gnomad AFR exome

AF:

0.000112

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00254

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

AN:

680418

Hom.:

Cov.:

AF XY:

0.0000993

AC XY:

AN XY:

352508

show subpopulations

African (AFR)

AF:

0.000110

AC:

AN:

18106

American (AMR)

AF:

0.000183

AC:

AN:

32842

Ashkenazi Jewish (ASJ)

AF:

0.00244

AC:

AN:

18450

East Asian (EAS)

AF:

0.0000311

AC:

AN:

32120

South Asian (SAS)

AF:

0.0000677

AC:

AN:

59106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2624

European-Non Finnish (NFE)

AF:

0.0000340

AC:

AN:

441020

Other (OTH)

AF:

0.000206

AC:

AN:

33952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000553

AC:

AN:

90450

Hom.:

Cov.:

AF XY:

0.0000243

AC XY:

AN XY:

41182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22112

American (AMR)

AF:

0.00

AC:

AN:

7908

Ashkenazi Jewish (ASJ)

AF:

0.00123

AC:

AN:

2446

East Asian (EAS)

AF:

0.00

AC:

AN:

3256

South Asian (SAS)

AF:

0.00

AC:

AN:

2236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5702

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0000223

AC:

AN:

44792

Other (OTH)

AF:

0.000931

AC:

AN:

1074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000360

Hom.:

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000118

AC:

ExAC

AF:

0.0000859

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Gaucher disease type I (7)

not provided (5)

Gaucher disease (4)

Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset (1)

Gaucher disease type II;C0268251:Gaucher disease type III;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I (1)

not specified (1)

Parkinson disease, late-onset (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.92

Eigen_PC

Benign

-0.84

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.33

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.46

PhyloP100

0.83

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.8

REVEL

Uncertain

0.57

Sift

Benign

0.052

Sift4G

Benign

0.18

Polyphen

0.49

Vest4

0.68

MVP

0.79

MPC

0.99

ClinPred

0.018

GERP RS

1.2

Varity_R

0.13

gMVP

0.67

Mutation Taster

=3/97

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over