rs79603348

Variant names:

• chr3-32996622-T-C
• rs79603348
• NM_000404.4:c.*423A>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_000404.4(GLB1):​c.*423A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000889 in 254,086 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: GLB1 NM_000404.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.0180
• Publications: 0 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: ClinGen, Myriad Women’s Health
• GM1 gangliosidosis type 3

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

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

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

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00139 (211/152342) while in subpopulation AFR AF = 0.00491 (204/41580). AF 95% confidence interval is 0.00435. There are 1 homozygotes in GnomAd4. There are 104 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLB1	NM_000404.4	MANE Select	c.*423A>G		3_prime_UTR	Exon 16 of 16	NP_000395.3
	GLB1	NM_001317040.2		c.*423A>G		3_prime_UTR	Exon 17 of 17	NP_001303969.2
	GLB1	NM_001079811.3		c.*423A>G		3_prime_UTR	Exon 16 of 16	NP_001073279.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLB1	ENST00000307363.10	TSL:1 MANE Select	c.*423A>G		3_prime_UTR	Exon 16 of 16	ENSP00000306920.4	P16278
	GLB1	ENST00000399402.7	TSL:2	c.*423A>G		3_prime_UTR	Exon 16 of 16	ENSP00000382333.2	P16278
	GLB1	ENST00000307377.12	TSL:1	c.*423A>G		downstream_gene	N/A	ENSP00000305920.8	E7EQ29

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152224 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.000147 AC: 15 AN: 101744 Hom.: 0 Cov.: 0 AF XY: 0.000168 AC XY: 9 AN XY: 53508

African (AFR) AF: 0.00399 AC: 13 AN: 3256

American (AMR) AF: 0.00 AC: 0 AN: 4256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2466

East Asian (EAS) AF: 0.00 AC: 0 AN: 4926

South Asian (SAS) AF: 0.00 AC: 0 AN: 15122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 354

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 61718

Other (OTH) AF: 0.000388 AC: 2 AN: 5158

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152342 Hom.: 1 Cov.: 33 AF XY: 0.00140 AC XY: 104 AN XY: 74492

African (AFR) AF: 0.00491 AC: 204 AN: 41580

American (AMR) AF: 0.000327 AC: 5 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000791 Hom.: 0

Bravo AF: 0.00139

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	GM1 gangliosidosis (1)
-	1	-	Mucopolysaccharidosis, MPS-IV-B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	10
DANN	Benign	0.89
PhyloP100		-0.018

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: rs79603348; hg19: chr3-33038114;