rs34204221

Variant names:

• chr3-33065568-A-G
• rs34204221
• NM_000404.4:c.458-11T>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.458-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,562,346 control chromosomes in the GnomAD database, including 10,018 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (906 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9112 hom.)
• Consequence: GLB1 NM_000404.4 intron
• Scores: Splicing: ADA: 0.0001366
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.00600
• Publications: 8 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=-0.81).
• BP6: Variant 3-33065568-A-G is Benign according to our data. Variant chr3-33065568-A-G is described in ClinVar as Benign. ClinVar VariationId is 92909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 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.458-11T>C		intron	N/A	NP_000395.3
	GLB1	NM_001317040.2		c.602-11T>C		intron	N/A	NP_001303969.2
	GLB1	NM_001079811.3		c.368-11T>C		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.458-11T>C		intron	N/A	ENSP00000306920.4
	GLB1	ENST00000307377.12	TSL:1	c.246-11T>C		intron	N/A	ENSP00000305920.8
	GLB1	ENST00000399402.7	TSL:2	c.368-11T>C		intron	N/A	ENSP00000382333.2

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15585 AN: 152144 Hom.: 906 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.0954

Gnomad EAS AF: 0.0169

Gnomad SAS AF: 0.0528

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.121

Gnomad OTH AF: 0.0860

GnomAD2 exomes AF: 0.0872 AC: 14889 AN: 170666 AF XY: 0.0858

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0392

Gnomad ASJ exome AF: 0.0896

Gnomad EAS exome AF: 0.0168

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.0844

GnomAD4 exome AF: 0.110 AC: 155760 AN: 1410084 Hom.: 9112 Cov.: 32 AF XY: 0.109 AC XY: 75945 AN XY: 696458

African (AFR) AF: 0.101 AC: 3275 AN: 32316

American (AMR) AF: 0.0418 AC: 1588 AN: 37958

Ashkenazi Jewish (ASJ) AF: 0.0927 AC: 2356 AN: 25416

East Asian (EAS) AF: 0.0166 AC: 618 AN: 37252

South Asian (SAS) AF: 0.0485 AC: 3897 AN: 80386

European-Finnish (FIN) AF: 0.128 AC: 6378 AN: 49770

Middle Eastern (MID) AF: 0.0423 AC: 231 AN: 5460

European-Non Finnish (NFE) AF: 0.121 AC: 131339 AN: 1083188

Other (OTH) AF: 0.104 AC: 6078 AN: 58338

GnomAD4 genome AF: 0.103 AC: 15611 AN: 152262 Hom.: 906 Cov.: 32 AF XY: 0.0997 AC XY: 7420 AN XY: 74442

African (AFR) AF: 0.102 AC: 4219 AN: 41558

American (AMR) AF: 0.0568 AC: 869 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0954 AC: 331 AN: 3470

East Asian (EAS) AF: 0.0170 AC: 88 AN: 5186

South Asian (SAS) AF: 0.0528 AC: 255 AN: 4830

European-Finnish (FIN) AF: 0.126 AC: 1336 AN: 10598

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.121 AC: 8248 AN: 68010

Other (OTH) AF: 0.0851 AC: 180 AN: 2114

Alfa AF: 0.114 Hom.: 333

Bravo AF: 0.0968

Asia WGS AF: 0.0370 AC: 127 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Mucopolysaccharidosis, MPS-IV-B (2)
-	-	2	not provided (2)
-	-	1	GM1 gangliosidosis (1)
-	-	1	GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B (1)
-	-	1	Infantile GM1 gangliosidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.9
DANN	Benign	0.79
PhyloP100		0.0060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.060
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: rs34204221; hg19: chr3-33107060;