chr3-33014312-T-C

Position:

chr3-33014312-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_000404.4(GLB1):c.1480-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

GLB1
NM_000404.4 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.42

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:

GLB1 (HGNC:):

GLB1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.12487709 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.2, offset of 26, new splice context is: gtttctaacctgactctcAGttc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-33014312-T-C is Pathogenic according to our data. Variant chr3-33014312-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLB1	NM_000404.4 linkuse as main transcript	c.1480-2A>G		splice_acceptor_variant, intron_variant		ENST00000307363.10	NP_000395.3	P16278

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.1480-2A>G		splice_acceptor_variant, intron_variant		1	NM_000404.4	ENSP00000306920.4		P16278

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000122

AC:

AN:

245574

Hom.:

AF XY:

0.00000750

AC XY:

AN XY:

133422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461344

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-B

Pathogenic:1

Pathogenic, criteria provided, single submitter

literature only

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

Jan 01, 2019

PVS1: splicing site (-2). PS3: Low in vivo enzymatic activity in homozygote. PM2: Very low frequency in ExAC -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2021

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10737981, 16941474, 30809705, 25557439, 21497194, 25525159) -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

This sequence change affects an acceptor splice site in intron 14 of the GLB1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587776526, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with GLB1-related conditions (PMID: 10737981, 21497194, 25557439). ClinVar contains an entry for this variant (Variation ID: 946). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10737981). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

GM1 gangliosidosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 20, 2020

Variant summary: GLB1 c.1480-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes a 5 splicing donor site. Four predict the variant abolishes a 3 acceptor site. In agreement with this, at least one publication reports experimental evidence that this variant affects mRNA splicing (Morrone_2000). The variant allele was found at a frequency of 1.2e-05 in 245574 control chromosomes (gnomAD). c.1480-2A>G has been reported in the literature in multiple individuals (both homozygous and compound heterozygous) affected with GM1 Gangliosidosis (Morrone_2000, Santamaria_2006, Utz_2015, Caciotti_2011) and in at least one individual (compound heterozygous) with MorquioB (Caciotti_2011). Most of the GM1 Gangliosidosis patients were of infantile phenotype. These data indicate that the variant is very likely to be associated with disease. Enzymatic activity from patient derived (who were homozygous for this variant) fibroblasts and leukocytes were found to have very low activity (Morrone_2000, Santamaria_2006). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 04, 2022

- -

GM1-gangliosidosis, type I, with cardiac involvement

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2000

- -

Infantile GM1 gangliosidosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type I GM1-gangliosidosis (MIM#230500). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Sequencing of cDNA obtained from patient’s RNA revealed the intronic retention of 28bp, leading to a frameshift and premature termination codon (PMID: 10737981). (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (3 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has been reported as pathogenic in at least five patients, in a homozygous or compound heterozygous state, with either GM1-gangliosidosis, type I (MIM#230500) or mucopolysaccharidosis type IVB (Morquio) (MIM#253010) (ClinVar, HGMD, PMIDs: 10737981, 16941474, 21497194, 30809705). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. The enzymatic activity of beta-galactosidase was reduced to 1% of controls in patient cells (PMID: 10737981). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_000404.3:c.1445G>A; p.(Arg482His)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited [(LABID/by trio analysis)]. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.71

Position offset: 26

DS_AL_spliceai

1.0

Position offset: -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