rs7614776

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000404.4(GLB1):c.34T>C(p.Leu12=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 1,612,206 control chromosomes in the GnomAD database, including 638,460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.89 ( 60318 hom., cov: 38)

Exomes 𝑓: 0.89 ( 578142 hom. )

Consequence

GLB1
NM_000404.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: 0.792

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 3-33097052-A-G is Benign according to our data. Variant chr3-33097052-A-G is described in ClinVar as [Benign]. Clinvar id is 92905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33097052-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.792 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4 linkuse as main transcript	c.34T>C	p.Leu12=	synonymous_variant	1/16	ENST00000307363.10
TMPPE	NM_001039770.3 linkuse as main transcript	c.-442T>C		5_prime_UTR_variant	1/2	ENST00000342462.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.34T>C	p.Leu12=	synonymous_variant	1/16	1	NM_000404.4	P2
TMPPE	ENST00000342462.5 linkuse as main transcript	c.-442T>C		5_prime_UTR_variant	1/2	2	NM_001039770.3	P1	Q6ZT21-1

Frequencies

GnomAD3 genomes

AF:

0.889

AC:

135240

AN:

152122

Hom.:

60287

Cov.:

show subpopulations

Gnomad AFR

AF:

0.866

Gnomad AMI

AF:

0.921

Gnomad AMR

AF:

0.944

Gnomad ASJ

AF:

0.908

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.949

Gnomad FIN

AF:

0.873

Gnomad MID

AF:

0.959

Gnomad NFE

AF:

0.879

Gnomad OTH

AF:

0.906

GnomAD3 exomes

AF:

0.909

AC:

222982

AN:

245356

Hom.:

101581

AF XY:

0.910

AC XY:

121644

AN XY:

133648

show subpopulations

Gnomad AFR exome

AF:

0.866

Gnomad AMR exome

AF:

0.959

Gnomad ASJ exome

AF:

0.913

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.954

Gnomad FIN exome

AF:

0.871

Gnomad NFE exome

AF:

0.879

Gnomad OTH exome

AF:

0.908

GnomAD4 exome

AF:

0.889

AC:

1298544

AN:

1459976

Hom.:

578142

Cov.:

AF XY:

0.891

AC XY:

647051

AN XY:

726342

show subpopulations

Gnomad4 AFR exome

AF:

0.862

Gnomad4 AMR exome

AF:

0.956

Gnomad4 ASJ exome

AF:

0.911

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.952

Gnomad4 FIN exome

AF:

0.871

Gnomad4 NFE exome

AF:

0.879

Gnomad4 OTH exome

AF:

0.895

GnomAD4 genome

AF:

0.889

AC:

135320

AN:

152230

Hom.:

60318

Cov.:

AF XY:

0.892

AC XY:

66418

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.865

Gnomad4 AMR

AF:

0.944

Gnomad4 ASJ

AF:

0.908

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.949

Gnomad4 FIN

AF:

0.873

Gnomad4 NFE

AF:

0.879

Gnomad4 OTH

AF:

0.907

Alfa

AF:

0.882

Hom.:

32048

Bravo

AF:

0.894

Asia WGS

AF:

0.968

AC:

3360

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	- -

Mucopolysaccharidosis, MPS-IV-B

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -

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	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided, no classification provided	phenotyping only	GenomeConnect - GM1	-	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

Invitae

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

BayesDel_noAF

Benign

-0.84

Cadd

Benign

6.5

Dann

Benign

0.65

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

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