chr3-32996691-A-G

Variant names:

• chr3-32996691-A-G
• rs12167
• NM_000404.4:c.*354T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.06
• Publications: 16 publications found

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 Gene-Disease associations (from GenCC):

• GM1 gangliosidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• GM1 gangliosidosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• mucopolysaccharidosis type 4B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• GM1 gangliosidosis type 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• GM1 gangliosidosis type 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 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_multiple_submitters_no_conflicts, 2 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 rank	MANE	Protein	UniProt
GLB1	NM_000404.4	c.*354T>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10	c.*354T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_000404.4	ENSP00000306920.4
GLB1	ENST00000399402.7	c.*354T>C		3_prime_UTR_variant	Exon 16 of 16	2		ENSP00000382333.2
GLB1	ENST00000307377.12	c.*354T>C		downstream_gene_variant		1		ENSP00000305920.8

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

African (AFR) AF: 0.0791 AC: 428 AN: 5410

American (AMR) AF: 0.302 AC: 2282 AN: 7554

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 1013 AN: 4506

East Asian (EAS) AF: 0.176 AC: 1371 AN: 7798

South Asian (SAS) AF: 0.242 AC: 7826 AN: 32286

European-Finnish (FIN) AF: 0.287 AC: 2367 AN: 8248

Middle Eastern (MID) AF: 0.164 AC: 107 AN: 652

European-Non Finnish (NFE) AF: 0.276 AC: 28509 AN: 103116

Other (OTH) AF: 0.261 AC: 2327 AN: 8930

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

African (AFR) AF: 0.0823 AC: 3421 AN: 41558

American (AMR) AF: 0.291 AC: 4446 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 695 AN: 3472

East Asian (EAS) AF: 0.187 AC: 967 AN: 5176

South Asian (SAS) AF: 0.247 AC: 1193 AN: 4828

European-Finnish (FIN) AF: 0.309 AC: 3272 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19050 AN: 67988

Other (OTH) AF: 0.220 AC: 464 AN: 2112

Alfa AF: 0.259 Hom.: 11827

Bravo AF: 0.212

Asia WGS AF: 0.253 AC: 880 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mucopolysaccharidosis, MPS-IV-B Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12167; hg19: chr3-33038183;