rs34421970

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000404.4(GLB1):c.1306C>T(p.Leu436Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,613,982 control chromosomes in the GnomAD database, including 159 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 Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L436V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0094 ( 6 hom., cov: 31)

Exomes 𝑓: 0.013 ( 153 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.568

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 -18 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 2 uncertain in NM_000404.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0032697916).

BP6

Variant 3-33018489-G-A is Benign according to our data. Variant chr3-33018489-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33018489-G-A is described in Lovd as [Benign]. Variant chr3-33018489-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00939 (1429/152118) while in subpopulation NFE AF= 0.0142 (964/67998). AF 95% confidence interval is 0.0134. There are 6 homozygotes in gnomad4. There are 683 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4 linkuse as main transcript	c.1306C>T	p.Leu436Phe	missense_variant	13/16	ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.1306C>T	p.Leu436Phe	missense_variant	13/16	1	NM_000404.4	P2

Frequencies

GnomAD3 genomes

AF:

0.00943

AC:

1433

AN:

152000

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00232

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00676

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00868

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0142

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.0115

AC:

2868

AN:

249586

Hom.:

AF XY:

0.0115

AC XY:

1562

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00492

Gnomad ASJ exome

AF:

0.0365

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00673

Gnomad FIN exome

AF:

0.0113

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0139

GnomAD4 exome

AF:

0.0132

AC:

19249

AN:

1461864

Hom.:

153

Cov.:

AF XY:

0.0129

AC XY:

9400

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00505

Gnomad4 ASJ exome

AF:

0.0388

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00664

Gnomad4 FIN exome

AF:

0.0122

Gnomad4 NFE exome

AF:

0.0143

Gnomad4 OTH exome

AF:

0.0121

GnomAD4 genome

AF:

0.00939

AC:

1429

AN:

152118

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

683

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00231

Gnomad4 AMR

AF:

0.00675

Gnomad4 ASJ

AF:

0.0349

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00868

Gnomad4 NFE

AF:

0.0142

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0133

Hom.:

Bravo

AF:

0.00915

TwinsUK

AF:

0.0143

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.00303

AC:

ESP6500EA

AF:

0.0140

AC:

117

ExAC

AF:

0.0122

AC:

1472

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.0135

EpiControl

AF:

0.0126

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -
Likely benign, no assertion criteria provided	research	Blueprint Genetics	Mar 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 29, 2019	This variant is associated with the following publications: (PMID: 16941474, 12644936) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2023	- -

GLB1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2019

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). -

Mucopolysaccharidosis, MPS-IV-B

Benign:1

Likely 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Jan 04, 2018

- -

GM1 gangliosidosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

0.0080

DANN

Benign

0.34

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.059

.;.;T

MetaRNN

Benign

0.0033

T;T;T

MetaSVM

Benign

-0.33

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.89

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.82

T;T;T

Sift4G

Benign

0.62

T;T;T

Polyphen

0.0010

.;.;B

Vest4

0.070

MPC

0.26

ClinPred

0.0062

GERP RS

-11

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.75

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