rs587776525

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_001039770.3(TMPPE):c.-399dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,611,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

TMPPE
NM_001039770.3 5_prime_UTR

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 3.14

Publications

8 publications found

Variant links:

Genes affected

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]

TMPPE links:

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: Myriad Women’s Health, ClinGen
GM1 gangliosidosis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
mucopolysaccharidosis type 4B
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), 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: Orphanet, Genomics England PanelApp

GLB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 3-33097008-T-TA is Pathogenic according to our data. Variant chr3-33097008-T-TA is described in ClinVar as Pathogenic. ClinVar VariationId is 936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPPE	NM_001039770.3 link	c.-399dupT		5_prime_UTR_variant	Exon 1 of 2	ENST00000342462.5	NP_001034859.2
GLB1	NM_000404.4 link	c.75+2dupT		splice_donor_variant, intron_variant	Intron 1 of 15	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPPE	ENST00000342462.5 link	c.-399dupT		5_prime_UTR_variant	Exon 1 of 2	2	NM_001039770.3	ENSP00000343398.4
GLB1	ENST00000307363.10 link	c.75+2dupT		splice_donor_variant, intron_variant	Intron 1 of 15	1	NM_000404.4	ENSP00000306920.4

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000201

AC:

AN:

243514

AF XY:

0.000256

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00132

Gnomad NFE exome

AF:

0.000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000145

AC:

211

AN:

1459288

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

726032

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33278

American (AMR)

AF:

0.0000225

AC:

AN:

44440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39544

South Asian (SAS)

AF:

0.000244

AC:

AN:

85932

European-Finnish (FIN)

AF:

0.00120

AC:

AN:

53350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000107

AC:

119

AN:

1110700

Other (OTH)

AF:

0.0000830

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

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:

0.000197

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41582

American (AMR)

AF:

0.00

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00207

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile GM1 gangliosidosis

Pathogenic:5

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed splice region c.75+2dup variant in GLB1 gene has been reported previously in homozygous or compound heterozygous state in individual(s) affected with GM1 gangliosidosis (Mishra et al., 2021). This variant is reported with the allele frequency of 0.02% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This splice region variant in intron 1 affects the splicing. The spliceAI tool predicts that this splice site variant is damaging. Studies have shown that this variant results in retention of 20bp of intron1 and introduces a premature termination codon (Morrone et al., 1994). For these reasons, this variant has been classified as Pathogenic. -

Aug 29, 2017

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0209 - Splice variant (canonical or non-canonical) proven to affect splicing/expression of the transcript with uncertain effect on protein structure (intron 1 of 15). Functional studies have proven this variant results in two new mRNA transcripts; a frameshift which is predicted to undergo nonsense mediated decay (PMID: 8198123), and the inframe skipping of exon 2 (PMID: 8199591). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (58 heterozygotes, 0 homozygotes). (P) 0505 - Abnormal splicing is predicted by in silico tools. (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic in multiple patients with GM1 gangliosidosis. Homozygous patients, or those in compound heterozygous with a truncating variant, had severe, infantile onset disease. A patient in compound heterozygous with a missense variant had a milder form of disease (ClinVar, PMID: 8198123, PMID: 8199591, PMID: 21497194). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Jun 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GM1 gangliosidosis type 3

Pathogenic:1

Jun 01, 1994

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Inborn genetic diseases

Pathogenic:1

Jul 08, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.75+2dupT variant results from a duplication of one nucleotide (T) between positions +2 and +3 after coding exon 1 of the GLB1 gene. This variant does not change the sequence of the canonical donor at this splice site. Based on data from gnomAD, the TT allele has an overall frequency of 0.021% (58/274876) total alleles studied. The highest observed frequency was 0.133% (33/24736) of European (Finnish) alleles. This variant has been identified in the homozygous state and/or in conjunction with other GLB1 variant(s) in individual(s) with features consistent with autosomal recessive GLB1-related disorders; in at least one instance, the variants were identified in trans (Chakraborty, 1994; Myers, 2018; Tebani, 2022). This nucleotide position is highly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Chakraborty, 1994; Morrone, 1994). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Mucopolysaccharidosis, MPS-IV-B

Pathogenic:1

May 11, 2018

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GLB1 c.75+2dupT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 0.00021 in 271704 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in GLB1 causing GM1 gangliosidosis (0.00021 vs 0.002), allowing no conclusion about variant significance. c.75+2dupT has been reported in the literature in multiple individuals affected with GM1 gangliosidosis. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:1

Jan 15, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant results in activation of a cryptic splice donor site and insertion of 20 base pairs of intronic sequence, resulting in a frameshift and protein truncation (Chakraborty et al., 1994; Morrone et al., 1994); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 8199591, 33737400, 21497194, 29352662, 30408610, 25936995, 29160035, 28476546, 31761138, 33942996, 33240792, 33558080, 8198123) -

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

Pathogenic:1

Sep 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 1 of the GLB1 gene. It does not directly change the encoded amino acid sequence of the GLB1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs766823411, gnomAD 0.1%). This variant has been observed in individuals with GM1 gangliosidosis (PMID: 8198123, 8199591, 29160035). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 936). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in retention of 20bp of intron1, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 8198123, 8199591). For these reasons, this variant has been classified as Pathogenic. -

GM1 gangliosidosis type 2

Pathogenic:1

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The splice site c.75+2dup variant in the GLB1 gene has been reported in a compound heterozygous state in an individual affected with GM1 gangliosidosis (Myers KA. et al., 2018). Experimental studies have shown that this variant disrupts mRNA splicing (Morrone A. et al., 1994). This variant is reported with the allele frequency (0.02%) in the gnomAD and is novel (not in any individuals) in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. This variant affects the invariant GT donor splice site. This nucleotide change in GLB1 is predicted to be conserved across species. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.1

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.75

Position offset: -16

DS_DL_spliceai

0.95

Position offset: 3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over