rs4302331

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 167145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33014229-A-G is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLB1	NM_000404.4 linkuse as main transcript	c.1561T>C	p.Cys521Arg	missense_variant	15/16	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.1561T>C	p.Cys521Arg	missense_variant	15/16	1	NM_000404.4	ENSP00000306920	P2

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

GnomAD3 exomes

AF:

0.983

AC:

243454

AN:

247642

Hom.:

120002

AF XY:

0.987

AC XY:

132858

AN XY:

134558

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 SAS exome

AF:

0.999

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

Gnomad4 AFR exome

AF:

0.773

Gnomad4 AMR exome

AF:

0.985

Gnomad4 ASJ exome

AF:

0.999

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.999

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

0.999

Gnomad4 OTH exome

AF:

0.984

GnomAD4 genome

AF:

0.936

AC:

142526

AN:

152198

Hom.:

67438

Cov.:

AF XY:

0.938

AC XY:

69839

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.781

Gnomad4 AMR

AF:

0.974

Gnomad4 ASJ

AF:

0.999

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.999

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.999

Gnomad4 OTH

AF:

0.954

Alfa

AF:

0.985

Hom.:

114901

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:2Other:1

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2019	This variant is associated with the following publications: (PMID: 15714521, 10338095, 17664528, 20981092, 27884173) -
not provided, no classification provided	phenotyping only	GenomeConnect - GM1	-	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. -

Mucopolysaccharidosis, MPS-IV-B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Infantile GM1 gangliosidosis

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

GM1 gangliosidosis type 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

GM1 gangliosidosis type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.4

DANN

Benign

0.47

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.023

.;.;T

MetaRNN

Benign

7.2e-7

T;T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

1.7

N;N;N

REVEL

Benign

0.13

Sift

Benign

0.75

T;T;T

Sift4G

Benign

0.53

T;T;T

Polyphen

0.0

.;.;B

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over