3-33014196-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000404.4(GLB1):c.1594A>G(p.Ser532Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.055 in 1,614,094 control chromosomes in the GnomAD database, including 2,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.050 ( 233 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2470 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: -2.81

Publications

22 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 -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 0.79419 (below the threshold of 3.09). Trascript score misZ: 1.1264 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 4B, GM1 gangliosidosis, GM1 gangliosidosis type 2, GM1 gangliosidosis type 3, GM1 gangliosidosis type 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017570257).

BP6

Variant 3-33014196-T-C is Benign according to our data. Variant chr3-33014196-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLB1	NM_000404.4 link	c.1594A>G	p.Ser532Gly	missense_variant	Exon 15 of 16	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 link	c.1594A>G	p.Ser532Gly	missense_variant	Exon 15 of 16	1	NM_000404.4	ENSP00000306920.4

Frequencies

GnomAD3 genomes

AF:

0.0502

AC:

7630

AN:

152094

Hom.:

233

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0336

Gnomad AMI

AF:

0.171

Gnomad AMR

AF:

0.0648

Gnomad ASJ

AF:

0.0764

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0125

Gnomad FIN

AF:

0.0405

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0617

Gnomad OTH

AF:

0.0608

GnomAD2 exomes

AF:

0.0470

AC:

11658

AN:

248130

AF XY:

0.0464

show subpopulations

Gnomad AFR exome

AF:

0.0310

Gnomad AMR exome

AF:

0.0404

Gnomad ASJ exome

AF:

0.0907

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.0421

Gnomad NFE exome

AF:

0.0647

Gnomad OTH exome

AF:

0.0629

GnomAD4 exome

AF:

0.0555

AC:

81160

AN:

1461882

Hom.:

2470

Cov.:

AF XY:

0.0544

AC XY:

39585

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0348

AC:

1166

AN:

33480

American (AMR)

AF:

0.0426

AC:

1904

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0925

AC:

2417

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0110

AC:

949

AN:

86258

European-Finnish (FIN)

AF:

0.0418

AC:

2234

AN:

53420

Middle Eastern (MID)

AF:

0.0719

AC:

415

AN:

5768

European-Non Finnish (NFE)

AF:

0.0617

AC:

68661

AN:

1112000

Other (OTH)

AF:

0.0564

AC:

3409

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

5601

11202

16802

22403

28004

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2436

4872

7308

9744

12180

<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:

0.0501

AC:

7629

AN:

152212

Hom.:

233

Cov.:

AF XY:

0.0478

AC XY:

3555

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0336

AC:

1394

AN:

41534

American (AMR)

AF:

0.0647

AC:

989

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0764

AC:

265

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0127

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0405

AC:

430

AN:

10606

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0616

AC:

4192

AN:

68012

Other (OTH)

AF:

0.0601

AC:

127

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

377

754

1130

1507

1884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0581

Hom.:

555

Bravo

AF:

0.0526

TwinsUK

AF:

0.0583

AC:

216

ALSPAC

AF:

0.0599

AC:

231

ESP6500AA

AF:

0.0331

AC:

133

ESP6500EA

AF:

0.0607

AC:

504

ExAC

AF:

0.0465

AC:

5619

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0698

EpiControl

AF:

0.0741

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jul 13, 2018

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

Significance:Benign

Review Status:no assertion criteria provided

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

not provided

Benign:3Other:1

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely 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.

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17664528, 10839995)

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine 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

GLB1-related disorder

Benign:1

Mar 26, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

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.

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

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.046

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0

.;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.0

.;.;T

MetaRNN

Benign

0.0018

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

-2.8

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.79

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.38

T;T;T

Sift4G

Benign

0.33

T;T;T

Vest4

0.044

ClinPred

0.00052

GERP RS

-6.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.31

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over