Genetic Variant GBA1:c.*92G>A (chr1-155234903-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_000157.4(GBA1):c.*92G>A variant causes a 3 prime UTR 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 0.0071 ( 1 hom., cov: 4)

Exomes 𝑓: 0.012 ( 39 hom. )

Failed GnomAD Quality Control

Consequence

GBA1
NM_000157.4 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.523

Publications

7 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 1-155234903-C-T is Benign according to our data. Variant chr1-155234903-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1809693.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0121 (5040/416414) while in subpopulation NFE AF = 0.014 (3437/245778). AF 95% confidence interval is 0.0136. There are 39 homozygotes in GnomAdExome4. There are 2569 alleles in the male GnomAdExome4 subpopulation. Median coverage is 3. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 39 AD,AR gene

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	Effect	Exon Rank	Protein	UniProt
GBA1	NM_000157.4	MANE Select	c.*92G>A	3_prime_UTR	Exon 11 of 11	NP_000148.2	P04062-1
GBA1	NM_001005741.3		c.*92G>A	3_prime_UTR	Exon 12 of 12	NP_001005741.1	P04062-1
GBA1	NM_001005742.3		c.*92G>A	3_prime_UTR	Exon 12 of 12	NP_001005742.1	P04062-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GBA1	ENST00000368373.8	TSL:1 MANE Select	c.*92G>A	3_prime_UTR	Exon 11 of 11	ENSP00000357357.3	P04062-1
GBA1	ENST00000327247.9	TSL:1	c.*92G>A	3_prime_UTR	Exon 12 of 12	ENSP00000314508.5	P04062-1
GBA1	ENST00000948997.1		c.*92G>A	3_prime_UTR	Exon 13 of 13	ENSP00000619056.1

Frequencies

GnomAD3 genomes

AF:

0.00705

AC:

129

AN:

18300

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00468

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00970

Gnomad ASJ

AF:

0.00830

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0146

Gnomad FIN

AF:

0.00319

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00822

Gnomad OTH

AF:

0.00313

GnomAD4 exome

AF:

0.0121

AC:

5040

AN:

416414

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

2569

AN XY:

219344

show subpopulations

African (AFR)

AF:

0.00451

AC:

AN:

12404

American (AMR)

AF:

0.0121

AC:

241

AN:

19964

Ashkenazi Jewish (ASJ)

AF:

0.00812

AC:

105

AN:

12934

East Asian (EAS)

AF:

0.00971

AC:

271

AN:

27902

South Asian (SAS)

AF:

0.00902

AC:

415

AN:

46016

European-Finnish (FIN)

AF:

0.00714

AC:

182

AN:

25498

Middle Eastern (MID)

AF:

0.00781

AC:

AN:

1792

European-Non Finnish (NFE)

AF:

0.0140

AC:

3437

AN:

245778

Other (OTH)

AF:

0.0132

AC:

319

AN:

24126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

243

486

730

973

1216

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00711

AC:

130

AN:

18284

Hom.:

Cov.:

AF XY:

0.00719

AC XY:

AN XY:

8344

show subpopulations

African (AFR)

AF:

0.00511

AC:

AN:

4304

American (AMR)

AF:

0.00970

AC:

AN:

1958

Ashkenazi Jewish (ASJ)

AF:

0.00830

AC:

AN:

482

East Asian (EAS)

AF:

0.00350

AC:

AN:

1144

South Asian (SAS)

AF:

0.0136

AC:

AN:

954

European-Finnish (FIN)

AF:

0.00319

AC:

AN:

1254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

120

European-Non Finnish (NFE)

AF:

0.00824

AC:

AN:

7650

Other (OTH)

AF:

0.00311

AC:

AN:

322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.0432

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

7.2

(source)

DANN

Benign

0.61

PhyloP100

0.52

Mutation Taster

=100/0

polymorphism

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over