rs371397760

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000404.4(GLB1):​c.1588C>T​(p.Arg530Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,614,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

3
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -1.36
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.007072538).
BP6
Variant 3-33014202-G-A is Benign according to our data. Variant chr3-33014202-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450616.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLB1NM_000404.4 linkuse as main transcriptc.1588C>T p.Arg530Cys missense_variant 15/16 ENST00000307363.10 NP_000395.3 P16278

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLB1ENST00000307363.10 linkuse as main transcriptc.1588C>T p.Arg530Cys missense_variant 15/161 NM_000404.4 ENSP00000306920.4 P16278

Frequencies

GnomAD3 genomes
AF:
0.000881
AC:
134
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00294
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000202
AC:
50
AN:
247966
Hom.:
0
AF XY:
0.000141
AC XY:
19
AN XY:
134670
show subpopulations
Gnomad AFR exome
AF:
0.00284
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000895
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000999
AC:
146
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.0000839
AC XY:
61
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00290
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000880
AC:
134
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.000887
AC XY:
66
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.00294
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00189
Alfa
AF:
0.000443
Hom.:
0
Bravo
AF:
0.000884
ESP6500AA
AF:
0.00150
AC:
6
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000248
AC:
30

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 26, 2017The R530C variant in the GLB1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. While not observed in the homozygous state, this variant is observed in 26/9804 (0.26%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The R530C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R530C as a variant of uncertain significance. -
Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
GLB1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 12, 2022This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 30, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
1.4
DANN
Uncertain
0.99
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.064
N
LIST_S2
Benign
0.21
.;.;T
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.0071
T;T;T
MetaSVM
Uncertain
-0.21
T
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-0.97
N;N;N
REVEL
Benign
0.28
Sift
Benign
0.19
T;T;T
Sift4G
Benign
0.063
T;T;T
Polyphen
0.99
.;.;D
Vest4
0.091
MVP
0.60
MPC
0.32
ClinPred
0.034
T
GERP RS
-1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
gMVP
0.51

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371397760; hg19: chr3-33055694; API