rs7637099

Variant names:

• chr3-33097057-G-A
• rs7637099
• NM_000404.4:c.29C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-33097057-G-A
• chr3-33097057-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000404.4(GLB1):​c.29C>T​(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 1,612,026 control chromosomes in the GnomAD database, including 286,322 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (20875 hom., cov: 36)
  • Exomes 𝑓: 0.60 (265447 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 0.206
• Publications: 42 publications found

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]

TMPPE (HGNC:33865): (transmembrane protein with metallophosphoesterase domain) Predicted to enable hydrolase activity and metal ion binding activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 0.79419 (below the threshold of 3.09). Trascript score misZ: 1.1264 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 4B, GM1 gangliosidosis, GM1 gangliosidosis type 2, GM1 gangliosidosis type 3, GM1 gangliosidosis type 1.
• BP4: Computational evidence support a benign effect (MetaRNN=1.3571978E-4).
• BP6: Variant 3-33097057-G-A is Benign according to our data. Variant chr3-33097057-G-A is described in ClinVar as Benign. ClinVar VariationId is 92904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLB1	NM_000404.4	c.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 16	ENST00000307363.10	NP_000395.3
TMPPE	NM_001039770.3	c.-447C>T		5_prime_UTR_variant	Exon 1 of 2	ENST00000342462.5	NP_001034859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10	c.29C>T	p.Pro10Leu	missense_variant	Exon 1 of 16	1	NM_000404.4	ENSP00000306920.4
TMPPE	ENST00000342462.5	c.-447C>T		5_prime_UTR_variant	Exon 1 of 2	2	NM_001039770.3	ENSP00000343398.4

Frequencies

GnomAD3 genomes AF: 0.481 AC: 73156 AN: 152100 Hom.: 20873 Cov.: 36

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.671

Gnomad EAS AF: 0.514

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.592

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.531

GnomAD2 exomes AF: 0.567 AC: 139166 AN: 245256 AF XY: 0.578

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.545

Gnomad ASJ exome AF: 0.679

Gnomad EAS exome AF: 0.513

Gnomad FIN exome AF: 0.595

Gnomad NFE exome AF: 0.622

Gnomad OTH exome AF: 0.605

GnomAD4 exome AF: 0.598 AC: 872782 AN: 1459818 Hom.: 265447 Cov.: 85 AF XY: 0.599 AC XY: 435262 AN XY: 726242

African (AFR) AF: 0.135 AC: 4518 AN: 33352

American (AMR) AF: 0.546 AC: 24308 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 17698 AN: 26032

East Asian (EAS) AF: 0.512 AC: 20249 AN: 39570

South Asian (SAS) AF: 0.572 AC: 49229 AN: 86024

European-Finnish (FIN) AF: 0.601 AC: 32052 AN: 53358

Middle Eastern (MID) AF: 0.635 AC: 3656 AN: 5758

European-Non Finnish (NFE) AF: 0.618 AC: 685979 AN: 1110894

Other (OTH) AF: 0.582 AC: 35093 AN: 60300

GnomAD4 genome AF: 0.481 AC: 73158 AN: 152208 Hom.: 20875 Cov.: 36 AF XY: 0.483 AC XY: 35950 AN XY: 74424

African (AFR) AF: 0.150 AC: 6247 AN: 41562

American (AMR) AF: 0.575 AC: 8786 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.671 AC: 2330 AN: 3470

East Asian (EAS) AF: 0.514 AC: 2654 AN: 5166

South Asian (SAS) AF: 0.548 AC: 2649 AN: 4832

European-Finnish (FIN) AF: 0.592 AC: 6277 AN: 10610

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.622 AC: 42287 AN: 67958

Other (OTH) AF: 0.530 AC: 1121 AN: 2114

Alfa AF: 0.572 Hom.: 93596

Bravo AF: 0.462

TwinsUK AF: 0.618 AC: 2290

ALSPAC AF: 0.625 AC: 2410

ESP6500AA AF: 0.160 AC: 641

ESP6500EA AF: 0.624 AC: 5237

ExAC AF: 0.560 AC: 67538

Asia WGS AF: 0.511 AC: 1769 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23806086, 10338095, 20981092, 20220177, 21228398, 15791924) -

May 25, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.29C>T (p.Pro10Leu) is a missense variant involves a non-conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.562 (66755/118674) which greatly exceeds the maximal expected allele frequency for a non-common pathogenic GLB1 variant (0.0009). Diagnostics centers and several published reports classified this variant as Likely Benign and Benign. Taken all together, the variant was classified as Benign. -

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mucopolysaccharidosis, MPS-IV-B Benign:3

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile GM1 gangliosidosis Benign:2

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GM1 gangliosidosis Benign:1 Other:1

-

GenomeConnect - GM1

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant identified in multiple registry participants. Variant interpreted as Benign and reported, most recently, on 08-10-2017 by lab or GTR ID Prevention Genetics. GenomeConnect - GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

GM1 gangliosidosis type 3 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GM1 gangliosidosis type 2 Benign:1

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	9.7
DANN	Benign	0.87
DEOGEN2	Benign	0.33	.;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.39	.;T;T;T
MetaRNN	Benign	0.00014	T;T;T;T
MetaSVM	Benign	-0.79	T
PhyloP100		0.21
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.32	N;N;D;N
REVEL	Uncertain	0.36
Sift	Benign	0.68	T;T;D;T
Sift4G	Benign	0.74	T;T;T;D
Polyphen		0.0	.;B;.;.
Vest4		0.035
MPC		0.76
ClinPred		0.0029	T
GERP RS		-0.13
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
gMVP		0.57
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7637099; hg19: chr3-33138549; COSMIC: COSV56561124; COSMIC: COSV56561124;