3-33021558-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000404.4(GLB1):c.1233+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,612,234 control chromosomes in the GnomAD database, including 37,411 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 3418 hom., cov: 32)

Exomes 𝑓: 0.21 ( 33993 hom. )

Consequence

GLB1
NM_000404.4 splice_region, intron

Scores

Splicing: ADA: 0.00002256

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 2.80

Publications

13 publications found

Variant links:

Genes affected

GLB1 (HGNC:4298): (galactosidase beta 1) This gene encodes a member of the glycosyl hydrolase 35 family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature lysosomal enzyme. This enzyme catalyzes the hydrolysis of a terminal beta-linked galactose residue from ganglioside substrates and other glycoconjugates. Mutations in this gene may result in GM1-gangliosidosis and Morquio B syndrome. [provided by RefSeq, Nov 2015]

GLB1 Gene-Disease associations (from GenCC):

GM1 gangliosidosis
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
GM1 gangliosidosis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
mucopolysaccharidosis type 4B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
GM1 gangliosidosis type 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
GM1 gangliosidosis type 2
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

GLB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 3-33021558-A-G is Benign according to our data. Variant chr3-33021558-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLB1	NM_000404.4 link	c.1233+8T>C		splice_region_variant, intron_variant	Intron 12 of 15	ENST00000307363.10	NP_000395.3	P16278

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 link	c.1233+8T>C		splice_region_variant, intron_variant	Intron 12 of 15	1	NM_000404.4	ENSP00000306920.4		P16278

Frequencies

GnomAD3 genomes

AF:

0.208

AC:

31572

AN:

152040

Hom.:

3417

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.197

Gnomad AMR

AF:

0.178

Gnomad ASJ

AF:

0.215

Gnomad EAS

AF:

0.0516

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.197

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.223

Gnomad OTH

AF:

0.197

GnomAD2 exomes

AF:

0.194

AC:

48010

AN:

246848

AF XY:

0.193

show subpopulations

Gnomad AFR exome

AF:

0.221

Gnomad AMR exome

AF:

0.193

Gnomad ASJ exome

AF:

0.224

Gnomad EAS exome

AF:

0.0569

Gnomad FIN exome

AF:

0.200

Gnomad NFE exome

AF:

0.220

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.213

AC:

310751

AN:

1460076

Hom.:

33993

Cov.:

AF XY:

0.211

AC XY:

153326

AN XY:

726178

show subpopulations

African (AFR)

AF:

0.222

AC:

7433

AN:

33466

American (AMR)

AF:

0.191

AC:

8510

AN:

44496

Ashkenazi Jewish (ASJ)

AF:

0.229

AC:

5957

AN:

26056

East Asian (EAS)

AF:

0.0598

AC:

2374

AN:

39686

South Asian (SAS)

AF:

0.157

AC:

13462

AN:

85956

European-Finnish (FIN)

AF:

0.202

AC:

10796

AN:

53328

Middle Eastern (MID)

AF:

0.153

AC:

879

AN:

5760

European-Non Finnish (NFE)

AF:

0.224

AC:

248708

AN:

1111000

Other (OTH)

AF:

0.209

AC:

12632

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

12174

24348

36521

48695

60869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8428

16856

25284

33712

42140

<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

AF:

0.208

AC:

31608

AN:

152158

Hom.:

3418

Cov.:

AF XY:

0.204

AC XY:

15167

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.222

AC:

9227

AN:

41504

American (AMR)

AF:

0.178

AC:

2715

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.215

AC:

745

AN:

3472

East Asian (EAS)

AF:

0.0518

AC:

268

AN:

5178

South Asian (SAS)

AF:

0.163

AC:

785

AN:

4822

European-Finnish (FIN)

AF:

0.197

AC:

2089

AN:

10578

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.223

AC:

15138

AN:

68004

Other (OTH)

AF:

0.199

AC:

421

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1283

2566

3850

5133

6416

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

346

692

1038

1384

1730

<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:

0.218

Hom.:

2461

Bravo

AF:

0.207

Asia WGS

AF:

0.139

AC:

482

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3Other:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

GenomeConnect - GM1

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 09-25-2014 by Lab or GTR ID 239772. GenomeConnect-GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

Mucopolysaccharidosis, MPS-IV-B

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GM1 gangliosidosis

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Infantile GM1 gangliosidosis

Benign:1

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.78

PhyloP100

2.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.030

Splicevardb

2.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over