Genetic Variant GBA1:p.Lys505Lys (chr1-155235091-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS1

The NM_000157.4(GBA1):c.1515G>A(p.Lys505Lys) variant causes a synonymous 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 benign (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 19)

Exomes 𝑓: 0.00015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GBA1
NM_000157.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.09

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant 1-155235091-C-T is Benign according to our data. Variant chr1-155235091-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 928836.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.09 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000145 (164/1129992) while in subpopulation EAS AF = 0.00455 (162/35598). AF 95% confidence interval is 0.00398. There are 0 homozygotes in GnomAdExome4. There are 84 alleles in the male GnomAdExome4 subpopulation. Median coverage is 15. This position passed quality control check.

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.1515G>A	p.Lys505Lys	synonymous	Exon 11 of 11	NP_000148.2	P04062-1
GBA1	NM_001005741.3		c.1515G>A	p.Lys505Lys	synonymous	Exon 12 of 12	NP_001005741.1	P04062-1
GBA1	NM_001005742.3		c.1515G>A	p.Lys505Lys	synonymous	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.1515G>A	p.Lys505Lys	synonymous	Exon 11 of 11	ENSP00000357357.3	P04062-1
GBA1	ENST00000327247.9	TSL:1	c.1515G>A	p.Lys505Lys	synonymous	Exon 12 of 12	ENSP00000314508.5	P04062-1
GBA1	ENST00000948997.1		c.1581G>A	p.Lys527Lys	synonymous	Exon 13 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes

AF:

0.0000546

AC:

AN:

128152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000988

Gnomad SAS

AF:

0.000574

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000616

GnomAD2 exomes

AF:

0.000189

AC:

AN:

243016

AF XY:

0.000167

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00256

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000145

AC:

164

AN:

1129992

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

AN XY:

570162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26850

American (AMR)

AF:

0.00

AC:

AN:

36626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23518

East Asian (EAS)

AF:

0.00455

AC:

162

AN:

35598

South Asian (SAS)

AF:

0.00

AC:

AN:

74984

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5140

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

827956

Other (OTH)

AF:

0.0000407

AC:

AN:

49174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.0000390

AC:

AN:

128258

Hom.:

Cov.:

AF XY:

0.0000490

AC XY:

AN XY:

61214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32990

American (AMR)

AF:

0.00

AC:

AN:

11884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3186

East Asian (EAS)

AF:

0.000991

AC:

AN:

4036

South Asian (SAS)

AF:

0.000288

AC:

AN:

3478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8750

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

61180

Other (OTH)

AF:

0.00

AC:

AN:

1646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.561

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

1.1

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over