rs34204221

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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

GLB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLB1	ENST00000307363.10	TSL:1 MANE Select	c.458-11T>C	intron	N/A	ENSP00000306920.4	P16278
GLB1	ENST00000307377.12	TSL:1	c.246-11T>C	intron	N/A	ENSP00000305920.8	E7EQ29
GLB1	ENST00000399402.7	TSL:2	c.368-11T>C	intron	N/A	ENSP00000382333.2	P16278

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15585

AN:

152144

Hom.:

906

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.109

AC XY:

75945

AN XY:

696458

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

8753

17506

26259

35012

43765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4698

9396

14094

18792

23490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.103

AC:

15611

AN:

152262

Hom.:

906

Cov.:

AF XY:

0.0997

AC XY:

7420

AN XY:

74442

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8248

AN:

68010

Other (OTH)

AF:

0.0851

AC:

180

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

717

1435

2152

2870

3587

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

186

372

558

744

930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.114

Hom.:

333

Bravo

AF:

0.0968

Asia WGS

AF:

0.0370

AC:

127

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Mucopolysaccharidosis, MPS-IV-B (2)

not provided (2)

GM1 gangliosidosis (1)

GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B (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

(source)

DANN

Benign

0.79

PhyloP100

0.0060

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over