dbSNP rs139730198: GLB1:c.*319G>A (chr3-32996726-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000404.4(GLB1):c.*319G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 375,242 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0082 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 21 hom. )

Consequence

GLB1
NM_000404.4 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -0.208

Publications

3 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, 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

GLB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 3-32996726-C-T is Benign according to our data. Variant chr3-32996726-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 344779.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00821 (1250/152344) while in subpopulation NFE AF = 0.0119 (812/68018). AF 95% confidence interval is 0.0113. There are 4 homozygotes in GnomAd4. There are 654 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

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.*319G>A	3_prime_UTR	Exon 16 of 16	NP_000395.3
GLB1	NM_001317040.2		c.*319G>A	3_prime_UTR	Exon 17 of 17	NP_001303969.2
GLB1	NM_001079811.3		c.*319G>A	3_prime_UTR	Exon 16 of 16	NP_001073279.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GLB1	ENST00000307363.10	TSL:1 MANE Select	c.*319G>A	3_prime_UTR	Exon 16 of 16	ENSP00000306920.4	P16278
GLB1	ENST00000399402.7	TSL:2	c.*319G>A	3_prime_UTR	Exon 16 of 16	ENSP00000382333.2	P16278
GLB1	ENST00000307377.12	TSL:1	c.*319G>A	downstream_gene	N/A	ENSP00000305920.8	E7EQ29

Frequencies

GnomAD3 genomes

AF:

0.00821

AC:

1250

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0192

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0119

Gnomad OTH

AF:

0.00765

GnomAD4 exome

AF:

0.00853

AC:

1902

AN:

222898

Hom.:

Cov.:

AF XY:

0.00811

AC XY:

969

AN XY:

119428

show subpopulations

African (AFR)

AF:

0.00182

AC:

AN:

6598

American (AMR)

AF:

0.00493

AC:

AN:

10142

Ashkenazi Jewish (ASJ)

AF:

0.0143

AC:

AN:

5954

East Asian (EAS)

AF:

0.00

AC:

AN:

10368

South Asian (SAS)

AF:

0.00159

AC:

AN:

37620

European-Finnish (FIN)

AF:

0.0201

AC:

209

AN:

10376

Middle Eastern (MID)

AF:

0.00357

AC:

AN:

840

European-Non Finnish (NFE)

AF:

0.0107

AC:

1387

AN:

129486

Other (OTH)

AF:

0.00834

AC:

AN:

11514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

170

254

339

424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00821

AC:

1250

AN:

152344

Hom.:

Cov.:

AF XY:

0.00878

AC XY:

654

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41586

American (AMR)

AF:

0.00660

AC:

101

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0192

AC:

204

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0119

AC:

812

AN:

68018

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

128

191

255

319

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0152

Hom.:

Bravo

AF:

0.00607

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

GM1 gangliosidosis (1)

Mucopolysaccharidosis, MPS-IV-B (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.3

(source)

DANN

Benign

0.74

PhyloP100

-0.21

Mutation Taster

=100/0

polymorphism

(source)

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

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