3-32978543-G-T

Variant names:

• chr3-32978543-G-T
• rs4678680
• NM_001393580.1:c.1735-16922C>A

Variant summary

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

The NM_001393580.1(GLB1):​c.1735-16922C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 152,030 control chromosomes in the GnomAD database, including 43,554 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 0.74 (43554 hom., cov: 31)
• Consequence: GLB1 NM_001393580.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.131
• Publications: 17 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLB1	NM_001393580.1	c.1735-16922C>A		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: 0.738 AC: 112152 AN: 151912 Hom.: 43514 Cov.: 31

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.816

Gnomad AMR AF: 0.797

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.899

Gnomad MID AF: 0.726

Gnomad NFE AF: 0.836

Gnomad OTH AF: 0.747

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

GnomAD4 genome AF: 0.738 AC: 112246 AN: 152030 Hom.: 43554 Cov.: 31 AF XY: 0.746 AC XY: 55445 AN XY: 74316

African (AFR) AF: 0.476 AC: 19708 AN: 41406

American (AMR) AF: 0.797 AC: 12165 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2684 AN: 3472

East Asian (EAS) AF: 0.923 AC: 4780 AN: 5178

South Asian (SAS) AF: 0.839 AC: 4050 AN: 4830

European-Finnish (FIN) AF: 0.899 AC: 9501 AN: 10574

Middle Eastern (MID) AF: 0.740 AC: 216 AN: 292

European-Non Finnish (NFE) AF: 0.836 AC: 56822 AN: 67998

Other (OTH) AF: 0.750 AC: 1576 AN: 2102

Alfa AF: 0.803 Hom.: 210662

Bravo AF: 0.718

Asia WGS AF: 0.828 AC: 2878 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.8
DANN	Benign	0.35
PhyloP100		0.13

Splicing

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

Other links and lift over

dbSNP: rs4678680; hg19: chr3-33020035;