3-33053481-C-A

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.792+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,614,012 control chromosomes in the GnomAD database, including 1,582 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 353 hom., cov: 32)

Exomes 𝑓: 0.035 ( 1229 hom. )

Consequence

GLB1
NM_000404.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.818

Publications

6 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=-0.82).

BP6

Variant 3-33053481-C-A is Benign according to our data. Variant chr3-33053481-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 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.792+10G>T	intron	N/A	NP_000395.3
GLB1	NM_001317040.2		c.936+10G>T	intron	N/A	NP_001303969.2
GLB1	NM_001079811.3		c.702+10G>T	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.792+10G>T	intron	N/A	ENSP00000306920.4	P16278
GLB1	ENST00000307377.12	TSL:1	c.399+10G>T	intron	N/A	ENSP00000305920.8	E7EQ29
GLB1	ENST00000399402.7	TSL:2	c.702+10G>T	intron	N/A	ENSP00000382333.2	P16278

Frequencies

GnomAD3 genomes

AF:

0.0548

AC:

8341

AN:

152084

Hom.:

347

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0360

Gnomad ASJ

AF:

0.0228

Gnomad EAS

AF:

0.0717

Gnomad SAS

AF:

0.0476

Gnomad FIN

AF:

0.0196

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0308

Gnomad OTH

AF:

0.0435

GnomAD2 exomes

AF:

0.0398

AC:

9930

AN:

249468

AF XY:

0.0394

show subpopulations

Gnomad AFR exome

AF:

0.114

Gnomad AMR exome

AF:

0.0361

Gnomad ASJ exome

AF:

0.0235

Gnomad EAS exome

AF:

0.0761

Gnomad FIN exome

AF:

0.0211

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0345

GnomAD4 exome

AF:

0.0353

AC:

51543

AN:

1461810

Hom.:

1229

Cov.:

AF XY:

0.0353

AC XY:

25699

AN XY:

727188

show subpopulations

African (AFR)

AF:

0.120

AC:

4010

AN:

33472

American (AMR)

AF:

0.0370

AC:

1656

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0222

AC:

580

AN:

26132

East Asian (EAS)

AF:

0.0719

AC:

2855

AN:

39698

South Asian (SAS)

AF:

0.0513

AC:

4424

AN:

86252

European-Finnish (FIN)

AF:

0.0212

AC:

1134

AN:

53414

Middle Eastern (MID)

AF:

0.0420

AC:

242

AN:

5768

European-Non Finnish (NFE)

AF:

0.0306

AC:

34078

AN:

1111954

Other (OTH)

AF:

0.0425

AC:

2564

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

2960

5920

8879

11839

14799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1396

2792

4188

5584

6980

<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:

0.0551

AC:

8379

AN:

152202

Hom.:

353

Cov.:

AF XY:

0.0541

AC XY:

4029

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.114

AC:

4714

AN:

41516

American (AMR)

AF:

0.0359

AC:

549

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0228

AC:

AN:

3470

East Asian (EAS)

AF:

0.0717

AC:

371

AN:

5176

South Asian (SAS)

AF:

0.0474

AC:

229

AN:

4828

European-Finnish (FIN)

AF:

0.0196

AC:

208

AN:

10602

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0308

AC:

2092

AN:

68000

Other (OTH)

AF:

0.0487

AC:

103

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

379

758

1138

1517

1896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0210

Hom.:

Bravo

AF:

0.0593

Asia WGS

AF:

0.0740

AC:

258

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Mucopolysaccharidosis, MPS-IV-B (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

-0.82

CADD

Benign

3.1

(source)

DANN

Benign

0.57

PhyloP100

0.82

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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