rs4678523

Variant names:

• chr3-32996229-T-C
• rs4678523
• NM_001393580.1:c.1734+17827A>G

Variant summary

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

The NM_001393580.1(GLB1):​c.1734+17827A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,034 control chromosomes in the GnomAD database, including 6,752 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 0.29 (6752 hom., cov: 33)
• Consequence: GLB1 NM_001393580.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.58
• Publications: 15 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLB1	NM_001393580.1	c.1734+17827A>G		intron_variant	Intron 15 of 15		NP_001380509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43770 AN: 151916 Hom.: 6749 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.428

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.325

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

GnomAD4 genome AF: 0.288 AC: 43807 AN: 152034 Hom.: 6752 Cov.: 33 AF XY: 0.287 AC XY: 21287 AN XY: 74296

African (AFR) AF: 0.227 AC: 9417 AN: 41504

American (AMR) AF: 0.370 AC: 5651 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 1484 AN: 3470

East Asian (EAS) AF: 0.116 AC: 600 AN: 5174

South Asian (SAS) AF: 0.254 AC: 1225 AN: 4814

European-Finnish (FIN) AF: 0.264 AC: 2781 AN: 10544

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21352 AN: 67950

Other (OTH) AF: 0.321 AC: 677 AN: 2106

Alfa AF: 0.312 Hom.: 20109

Bravo AF: 0.295

Asia WGS AF: 0.182 AC: 636 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.036
DANN	Benign	0.44
PhyloP100		-4.6

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4678523; hg19: chr3-33037721;