NM_000157.4:c.1606C>T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000157.4(GBA1):c.1606C>T(p.Gln536*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 11)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GBA1
NM_000157.4 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

Publications

2 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: Uncertain_significance. The variant received 2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0031 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

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.1606C>T	p.Gln536*	stop_gained	Exon 11 of 11	NP_000148.2	P04062-1
GBA1	NM_001005741.3		c.1606C>T	p.Gln536*	stop_gained	Exon 12 of 12	NP_001005741.1	P04062-1
GBA1	NM_001005742.3		c.1606C>T	p.Gln536*	stop_gained	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.1606C>T	p.Gln536*	stop_gained	Exon 11 of 11	ENSP00000357357.3	P04062-1
GBA1	ENST00000327247.9	TSL:1	c.1606C>T	p.Gln536*	stop_gained	Exon 12 of 12	ENSP00000314508.5	P04062-1
GBA1	ENST00000948997.1		c.1672C>T	p.Gln558*	stop_gained	Exon 13 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes

AF:

0.0000904

AC:

AN:

88538

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000370

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:

0.0000119

AC:

AN:

168572

AF XY:

0.0000112

show subpopulations

Gnomad AFR exome

AF:

0.000113

Gnomad AMR exome

AF:

0.0000393

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000750

AC:

AN:

666316

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

345698

show subpopulations

African (AFR)

AF:

0.000224

AC:

AN:

17848

American (AMR)

AF:

0.0000304

AC:

AN:

32856

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18290

East Asian (EAS)

AF:

0.00

AC:

AN:

32080

South Asian (SAS)

AF:

0.00

AC:

AN:

58670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2590

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

428638

Other (OTH)

AF:

0.00

AC:

AN:

33462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000790

AC:

AN:

88628

Hom.:

Cov.:

AF XY:

0.0000993

AC XY:

AN XY:

40290

show subpopulations

African (AFR)

AF:

0.000323

AC:

AN:

21704

American (AMR)

AF:

0.00

AC:

AN:

7756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2420

East Asian (EAS)

AF:

0.00

AC:

AN:

3180

South Asian (SAS)

AF:

0.00

AC:

AN:

2184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

43838

Other (OTH)

AF:

0.00

AC:

AN:

1076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.556

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000843

Hom.:

ExAC

AF:

0.0000259

AC:

ClinVar

ClinVar submissions

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

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.92

PhyloP100

3.2

Vest4

0.61

GERP RS

3.1

Mutation Taster

=35/165

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over