3-32996691-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000404.4(GLB1):c.*354T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 330,724 control chromosomes in the GnomAD database, including 10,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4406 hom., cov: 33)
  • Exomes 𝑓: 0.26 (6335 hom.)
• Consequence: GLB1 NM_000404.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.06

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-32996691-A-G is Benign according to our data. Variant chr3-32996691-A-G is described in ClinVar as [Benign]. Clinvar id is 344778.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4	c.*354T>C		3_prime_UTR_variant	16/16	ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10	c.*354T>C		3_prime_UTR_variant	16/16	1	NM_000404.4	P2
GLB1	ENST00000399402.7	c.*354T>C		3_prime_UTR_variant	16/16	2		A2
GLB1	ENST00000307377.12			downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33623 AN: 152106 Hom.: 4398 Cov.: 33

Gnomad AFR AF: 0.0824

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.219

GnomAD4 exome AF: 0.259 AC: 46230 AN: 178500 Hom.: 6335 Cov.: 2 AF XY: 0.257 AC XY: 24659 AN XY: 95814

Gnomad4 AFR exome AF: 0.0791

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.242

Gnomad4 FIN exome AF: 0.287

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.261

GnomAD4 genome AF: 0.221 AC: 33642 AN: 152224 Hom.: 4406 Cov.: 33 AF XY: 0.223 AC XY: 16580 AN XY: 74426

Gnomad4 AFR AF: 0.0823

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.220

Alfa AF: 0.263 Hom.: 8118

Bravo AF: 0.212

Asia WGS AF: 0.253 AC: 880 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-B 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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.84
Dann	Benign	0.81

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

Other links and lift over

dbSNP: rs12167; hg19: chr3-33038183;