rs13093698

Positions:

• chr3-33021558-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.1233+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,612,234 control chromosomes in the GnomAD database, including 37,411 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3418 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33993 hom.)
• Consequence: GLB1 NM_000404.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002256
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 2.80

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=-0.67).
• BP6: Variant 3-33021558-A-G is Benign according to our data. Variant chr3-33021558-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 92894.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33021558-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4	c.1233+8T>C		splice_region_variant, intron_variant		ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10	c.1233+8T>C		splice_region_variant, intron_variant		1	NM_000404.4	P2

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31572 AN: 152040 Hom.: 3417 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0516

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.194 AC: 48010 AN: 246848 Hom.: 4885 AF XY: 0.193 AC XY: 25822 AN XY: 133826

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.0569

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.213 AC: 310751 AN: 1460076 Hom.: 33993 Cov.: 33 AF XY: 0.211 AC XY: 153326 AN XY: 726178

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.191

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.0598

Gnomad4 SAS exome AF: 0.157

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.224

Gnomad4 OTH exome AF: 0.209

GnomAD4 genome AF: 0.208 AC: 31608 AN: 152158 Hom.: 3418 Cov.: 32 AF XY: 0.204 AC XY: 15167 AN XY: 74378

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.178

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.0518

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.223

Gnomad4 OTH AF: 0.199

Alfa AF: 0.218 Hom.: 2181

Bravo AF: 0.207

Asia WGS AF: 0.139 AC: 482 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - GM1	-	Variant interpreted as Benign and reported on 09-25-2014 by Lab or GTR ID 239772. 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. -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Mucopolysaccharidosis, MPS-IV-B Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
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. -

GM1 gangliosidosis 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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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	-0.67
CADD	Benign	12
DANN	Benign	0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.030
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: rs13093698; hg19: chr3-33063050;