rs34204221

Positions:

• chr3-33065568-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000404.4(GLB1):​c.458-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,562,346 control chromosomes in the GnomAD database, including 10,018 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (906 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9112 hom.)
• Consequence: GLB1 NM_000404.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001366
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.00600

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-33065568-A-G is Benign according to our data. Variant chr3-33065568-A-G is described in ClinVar as [Benign]. Clinvar id is 92909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33065568-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4	c.458-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10	c.458-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000404.4	P2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15585 AN: 152144 Hom.: 906 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0860

GnomAD3 exomes AF: 0.0872 AC: 14889 AN: 170666 Hom.: 777 AF XY: 0.0858 AC XY: 7796 AN XY: 90870

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0392

Gnomad ASJ exome AF: 0.0896

Gnomad EAS exome AF: 0.0168

Gnomad SAS exome AF: 0.0469

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.0844

GnomAD4 exome AF: 0.110 AC: 155760 AN: 1410084 Hom.: 9112 Cov.: 32 AF XY: 0.109 AC XY: 75945 AN XY: 696458

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.0418

Gnomad4 ASJ exome AF: 0.0927

Gnomad4 EAS exome AF: 0.0166

Gnomad4 SAS exome AF: 0.0485

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.121

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.103 AC: 15611 AN: 152262 Hom.: 906 Cov.: 32 AF XY: 0.0997 AC XY: 7420 AN XY: 74442

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0568

Gnomad4 ASJ AF: 0.0954

Gnomad4 EAS AF: 0.0170

Gnomad4 SAS AF: 0.0528

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.121

Gnomad4 OTH AF: 0.0851

Alfa AF: 0.114 Hom.: 327

Bravo AF: 0.0968

Asia WGS AF: 0.0370 AC: 127 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Mucopolysaccharidosis, MPS-IV-B Benign:2

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	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 16, 2015

- -

GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

GM1 gangliosidosis Benign: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. -

Infantile GM1 gangliosidosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Pars Genome Lab

Jun 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.060
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

Other links and lift over

dbSNP: rs34204221; hg19: chr3-33107060;