NM_000157.4:c.1601G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1PP2BP4_Moderate

The NM_000157.4(GBA1):c.1601G>A(p.Arg534His) 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 11)

Exomes 𝑓: 0.000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0570

Publications

1 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Gaucher disease type I
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
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: Uncertain_significance. The variant received 1 ACMG points.

PM1

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

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.09769955).

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.1601G>A	p.Arg534His	missense	Exon 11 of 11	NP_000148.2	P04062-1
GBA1	NM_001005741.3		c.1601G>A	p.Arg534His	missense	Exon 12 of 12	NP_001005741.1	P04062-1
GBA1	NM_001005742.3		c.1601G>A	p.Arg534His	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.1601G>A	p.Arg534His	missense	Exon 11 of 11	ENSP00000357357.3	P04062-1
GBA1	ENST00000327247.9	TSL:1	c.1601G>A	p.Arg534His	missense	Exon 12 of 12	ENSP00000314508.5	P04062-1
GBA1	ENST00000948997.1		c.1667G>A	p.Arg556His	missense	Exon 13 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

93004

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000571

AC:

AN:

175110

AF XY:

0.0000107

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000229

AC:

AN:

699764

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

361920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18424

American (AMR)

AF:

0.00

AC:

AN:

33024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18754

East Asian (EAS)

AF:

0.00

AC:

AN:

32208

South Asian (SAS)

AF:

0.000150

AC:

AN:

60178

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2670

European-Non Finnish (NFE)

AF:

0.0000153

AC:

AN:

456570

Other (OTH)

AF:

0.00

AC:

AN:

34586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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: AC0;AS_VQSR

AF:

0.00

AC:

AN:

93004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

42404

African (AFR)

AF:

0.00

AC:

AN:

22788

American (AMR)

AF:

0.00

AC:

AN:

8136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2488

East Asian (EAS)

AF:

0.00

AC:

AN:

3348

South Asian (SAS)

AF:

0.00

AC:

AN:

2312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5876

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

46024

Other (OTH)

AF:

0.00

AC:

AN:

1094

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.39

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.34

PhyloP100

0.057

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.53

Sift

Benign

0.43

Sift4G

Benign

0.25

Polyphen

0.0010

Vest4

0.097

MutPred

0.30

Loss of MoRF binding (P = 6e-04)

MVP

0.80

MPC

0.94

ClinPred

0.13

GERP RS

2.3

Varity_R

0.17

gMVP

0.44

Mutation Taster

=11/89

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over