3-33023847-G-A

Variant names:

• chr3-33023847-G-A
• rs7613051
• NM_000404.4:c.1143+404C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000404.4(GLB1):​c.1143+404C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 151,994 control chromosomes in the GnomAD database, including 5,285 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.25 (5285 hom., cov: 32)
• Consequence: GLB1 NM_000404.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.410
• Publications: 26 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000404.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLB1	NM_000404.4	MANE Select	c.1143+404C>T		intron	N/A	NP_000395.3
	GLB1	NM_001317040.2		c.1287+404C>T		intron	N/A	NP_001303969.2
	GLB1	NM_001079811.3		c.1053+404C>T		intron	N/A	NP_001073279.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLB1	ENST00000307363.10	TSL:1 MANE Select	c.1143+404C>T		intron	N/A	ENSP00000306920.4
	GLB1	ENST00000307377.12	TSL:1	c.750+404C>T		intron	N/A	ENSP00000305920.8
	GLB1	ENST00000399402.7	TSL:2	c.1053+404C>T		intron	N/A	ENSP00000382333.2

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38472 AN: 151876 Hom.: 5280 Cov.: 32

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.235

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.253 AC: 38511 AN: 151994 Hom.: 5285 Cov.: 32 AF XY: 0.254 AC XY: 18852 AN XY: 74278

African (AFR) AF: 0.301 AC: 12466 AN: 41416

American (AMR) AF: 0.195 AC: 2974 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 755 AN: 3470

East Asian (EAS) AF: 0.479 AC: 2469 AN: 5156

South Asian (SAS) AF: 0.314 AC: 1516 AN: 4826

European-Finnish (FIN) AF: 0.221 AC: 2338 AN: 10560

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15267 AN: 67972

Other (OTH) AF: 0.240 AC: 506 AN: 2112

Alfa AF: 0.232 Hom.: 18333

Bravo AF: 0.253

Asia WGS AF: 0.362 AC: 1256 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.3
DANN	Benign	0.65
PhyloP100		-0.41
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: rs7613051; hg19: chr3-33065339;