3-33058199-C-T

Position:

chr3-33058199-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM5BP4_StrongBS2

The NM_000404.4(GLB1):c.623G>A(p.Arg208His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,614,088 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

GLB1
NM_000404.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3

Conservation

PhyloP100: -0.479

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a disulfide_bond (size 35) in uniprot entity BGAL_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_000404.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077244937).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLB1	NM_000404.4 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	6/16	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10 linkuse as main transcript	c.623G>A	p.Arg208His	missense_variant	6/16	1	NM_000404.4	ENSP00000306920	P2

Frequencies

GnomAD3 genomes

AF:

0.00102

AC:

155

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00500

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.00114

AC:

284

AN:

249152

Hom.:

AF XY:

0.00108

AC XY:

146

AN XY:

135178

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00515

Gnomad NFE exome

AF:

0.00143

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00105

AC:

1529

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

733

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00524

Gnomad4 NFE exome

AF:

0.00108

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.00102

AC:

155

AN:

152230

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00500

Gnomad4 NFE

AF:

0.00140

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000866

Hom.:

Bravo

AF:

0.000555

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000974

AC:

ExAC

AF:

0.00117

AC:

141

EpiCase

AF:

0.000763

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The GLB1 p.Arg256His variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs111840209), ClinVar (classified as a VUS by Mayo Clinic Genetic Testing Laboratories for Infantile GM1 gangliosidosis, GM1 gangliosidosis type 2 and Gangliosidosis GM1 type 3) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 337 of 280546 chromosomes (1 homozygous) at a frequency of 0.001201 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 133 of 25036 chromosomes (freq: 0.005312), Other in 12 of 7134 chromosomes (freq: 0.001682), European (non-Finnish) in 190 of 128374 chromosomes (freq: 0.00148) and African in 1 of 24182 chromosomes (freq: 0.000041), Latino in 1 of 35346 chromosomes (freq: 0.000028), but was not observed in the Ashkenazi Jewish, East Asian or South Asian populations. The p.Arg256 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 09, 2023	BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Mucopolysaccharidosis, MPS-IV-B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

GM1 gangliosidosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

0.99

DANN

Benign

0.86

DEOGEN2

Uncertain

0.74

.;.;D;D

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.85

.;.;T;T

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.0077

T;T;T;T

MetaSVM

Uncertain

0.20

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Benign

0.25

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Uncertain

0.48

Sift

Benign

0.21

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Vest4

0.23

MVP

0.85

MPC

0.29

ClinPred

0.054

GERP RS

-8.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.72

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over