Genetic Variant GLB1:p.Cys521Arg (chr3-33014229-A-G) – ACMG Classification: Benign (-19 pts)

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.1561T>C(p.Cys521Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,614,086 control chromosomes in the GnomAD database, including 788,793 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C521Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.94 ( 67438 hom., cov: 30)

Exomes 𝑓: 0.99 ( 721355 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.385

Publications

41 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:

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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=7.181308E-7).

BP6

Variant 3-33014229-A-G is Benign according to our data. Variant chr3-33014229-A-G is described in ClinVar as Benign. ClinVar VariationId is 167145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLB1	NM_000404.4	MANE Select	c.1561T>C	p.Cys521Arg	missense	Exon 15 of 16	NP_000395.3
GLB1	NM_001317040.2		c.1705T>C	p.Cys569Arg	missense	Exon 16 of 17	NP_001303969.2
GLB1	NM_001079811.3		c.1471T>C	p.Cys491Arg	missense	Exon 15 of 16	NP_001073279.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLB1	ENST00000307363.10	TSL:1 MANE Select	c.1561T>C	p.Cys521Arg	missense	Exon 15 of 16	ENSP00000306920.4
GLB1	ENST00000307377.12	TSL:1	c.1168T>C	p.Cys390Arg	missense	Exon 12 of 13	ENSP00000305920.8
GLB1	ENST00000399402.7	TSL:2	c.1471T>C	p.Cys491Arg	missense	Exon 15 of 16	ENSP00000382333.2

Frequencies

GnomAD3 genomes

AF:

0.937

AC:

142425

AN:

152080

Hom.:

67394

Cov.:

show subpopulations

Gnomad AFR

AF:

0.781

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.974

Gnomad ASJ

AF:

0.999

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.999

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.959

Gnomad NFE

AF:

0.999

Gnomad OTH

AF:

0.954

GnomAD2 exomes

AF:

0.983

AC:

243454

AN:

247642

AF XY:

0.987

show subpopulations

Gnomad AFR exome

AF:

0.776

Gnomad AMR exome

AF:

0.987

Gnomad ASJ exome

AF:

0.999

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

0.998

Gnomad OTH exome

AF:

0.991

GnomAD4 exome

AF:

0.993

AC:

1451358

AN:

1461888

Hom.:

721355

Cov.:

AF XY:

0.994

AC XY:

722658

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.773

AC:

25883

AN:

33480

American (AMR)

AF:

0.985

AC:

44031

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

26111

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39700

AN:

39700

South Asian (SAS)

AF:

0.999

AC:

86203

AN:

86256

European-Finnish (FIN)

AF:

1.00

AC:

53420

AN:

53420

Middle Eastern (MID)

AF:

0.988

AC:

5694

AN:

5766

European-Non Finnish (NFE)

AF:

0.999

AC:

1110861

AN:

1112010

Other (OTH)

AF:

0.984

AC:

59455

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

592

1184

1776

2368

2960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21658

43316

64974

86632

108290

<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:

0.936

AC:

142526

AN:

152198

Hom.:

67438

Cov.:

AF XY:

0.938

AC XY:

69839

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.781

AC:

32407

AN:

41470

American (AMR)

AF:

0.974

AC:

14900

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.999

AC:

3467

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5170

AN:

5170

South Asian (SAS)

AF:

0.999

AC:

4815

AN:

4822

European-Finnish (FIN)

AF:

1.00

AC:

10628

AN:

10628

Middle Eastern (MID)

AF:

0.959

AC:

282

AN:

294

European-Non Finnish (NFE)

AF:

0.999

AC:

67928

AN:

68020

Other (OTH)

AF:

0.954

AC:

2017

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

387

774

1160

1547

1934

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

902

1804

2706

3608

4510

<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:

0.975

Hom.:

166119

Bravo

AF:

0.927

TwinsUK

AF:

0.998

AC:

3701

ALSPAC

AF:

0.998

AC:

3848

ESP6500AA

AF:

0.798

AC:

3216

ESP6500EA

AF:

0.998

AC:

8289

ExAC

AF:

0.980

AC:

118416

Asia WGS

AF:

0.988

AC:

3436

AN:

3478

EpiCase

AF:

0.998

EpiControl

AF:

0.998

ClinVar

Significance: Benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2Other:1

GenomeConnect - GM1

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 08-10-2017 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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 15714521, 10338095, 17664528, 20981092, 27884173)

Mucopolysaccharidosis, MPS-IV-B

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Infantile GM1 gangliosidosis

Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GM1 gangliosidosis type 3

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: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

GM1 gangliosidosis type 2

Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.4

(source)

DANN

Benign

0.47

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.023

MetaRNN

Benign

7.2e-7

MetaSVM

Benign

-0.97

PhyloP100

0.39

PrimateAI

Benign

0.25

PROVEAN

Benign

1.7

REVEL

Benign

0.13

Sift

Benign

0.75

Sift4G

Benign

0.53

Polyphen

0.0

Vest4

0.021

MPC

0.41

ClinPred

0.00053

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.70

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over