rs7637099

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.29C>T(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,612,026 control chromosomes in the GnomAD database, including 286,322 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.48 ( 20875 hom., cov: 36)

Exomes 𝑓: 0.60 ( 265447 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 0.206

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:

TMPPE (HGNC:33865): (transmembrane protein with metallophosphoesterase domain) Predicted to enable hydrolase activity and metal ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMPPE 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=1.3571978E-4).

BP6

Variant 3-33097057-G-A is Benign according to our data. Variant chr3-33097057-G-A is described in ClinVar as [Benign]. Clinvar id is 92904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33097057-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.617 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.29C>T	p.Pro10Leu	missense_variant	1/16	ENST00000307363.10	NP_000395.3
TMPPE	NM_001039770.3 linkuse as main transcript	c.-447C>T		5_prime_UTR_variant	1/2	ENST00000342462.5	NP_001034859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.29C>T	p.Pro10Leu	missense_variant	1/16	1	NM_000404.4	ENSP00000306920	P2
TMPPE	ENST00000342462.5 linkuse as main transcript	c.-447C>T		5_prime_UTR_variant	1/2	2	NM_001039770.3	ENSP00000343398	P1	Q6ZT21-1

Frequencies

GnomAD3 genomes

AF:

0.481

AC:

73156

AN:

152100

Hom.:

20873

Cov.:

show subpopulations

Gnomad AFR

AF:

0.151

Gnomad AMI

AF:

0.693

Gnomad AMR

AF:

0.574

Gnomad ASJ

AF:

0.671

Gnomad EAS

AF:

0.514

Gnomad SAS

AF:

0.549

Gnomad FIN

AF:

0.592

Gnomad MID

AF:

0.589

Gnomad NFE

AF:

0.622

Gnomad OTH

AF:

0.531

GnomAD3 exomes

AF:

0.567

AC:

139166

AN:

245256

Hom.:

41241

AF XY:

0.578

AC XY:

77253

AN XY:

133598

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.545

Gnomad ASJ exome

AF:

0.679

Gnomad EAS exome

AF:

0.513

Gnomad SAS exome

AF:

0.577

Gnomad FIN exome

AF:

0.595

Gnomad NFE exome

AF:

0.622

Gnomad OTH exome

AF:

0.605

GnomAD4 exome

AF:

0.598

AC:

872782

AN:

1459818

Hom.:

265447

Cov.:

AF XY:

0.599

AC XY:

435262

AN XY:

726242

show subpopulations

Gnomad4 AFR exome

AF:

0.135

Gnomad4 AMR exome

AF:

0.546

Gnomad4 ASJ exome

AF:

0.680

Gnomad4 EAS exome

AF:

0.512

Gnomad4 SAS exome

AF:

0.572

Gnomad4 FIN exome

AF:

0.601

Gnomad4 NFE exome

AF:

0.618

Gnomad4 OTH exome

AF:

0.582

GnomAD4 genome

AF:

0.481

AC:

73158

AN:

152208

Hom.:

20875

Cov.:

AF XY:

0.483

AC XY:

35950

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.150

Gnomad4 AMR

AF:

0.575

Gnomad4 ASJ

AF:

0.671

Gnomad4 EAS

AF:

0.514

Gnomad4 SAS

AF:

0.548

Gnomad4 FIN

AF:

0.592

Gnomad4 NFE

AF:

0.622

Gnomad4 OTH

AF:

0.530

Alfa

AF:

0.599

Hom.:

65623

Bravo

AF:

0.462

TwinsUK

AF:

0.618

AC:

2290

ALSPAC

AF:

0.625

AC:

2410

ESP6500AA

AF:

0.160

AC:

641

ESP6500EA

AF:

0.624

AC:

5237

ExAC

AF:

0.560

AC:

67538

Asia WGS

AF:

0.511

AC:

1769

AN:

3464

ClinVar

Significance: Benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 23806086, 10338095, 20981092, 20220177, 21228398, 15791924) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2016	Variant summary: The c.29C>T (p.Pro10Leu) is a missense variant involves a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.562 (66755/118674) which greatly exceeds the maximal expected allele frequency for a non-common pathogenic GLB1 variant (0.0009). Diagnostics centers and several published reports classified this variant as Likely Benign and Benign. Taken all together, the variant was classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mucopolysaccharidosis, MPS-IV-B

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
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	- -

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

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
not provided, no classification provided	phenotyping only	GenomeConnect - GM1	-	Variant identified in multiple registry participants. Variant interpreted as Benign and reported, most recently, on 08-10-2017 by lab or GTR ID Prevention Genetics. 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. Phenotypic details are available under supporting information. -

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

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.13

CADD

Benign

9.7

DANN

Benign

0.87

DEOGEN2

Benign

0.33

.;.;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.39

.;T;T;T

MetaRNN

Benign

0.00014

T;T;T;T

MetaSVM

Benign

-0.79

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.32

N;N;D;N

REVEL

Uncertain

0.36

Sift

Benign

0.68

T;T;D;T

Sift4G

Benign

0.74

T;T;T;D

Polyphen

0.0

.;B;.;.

Vest4

0.035

MPC

0.76

ClinPred

0.0029

GERP RS

-0.13

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

gMVP

0.57

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