rs7614776

Variant names:

• chr3-33097052-A-G
• rs7614776
• NM_001039770.3:c.-442T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039770.3(TMPPE):​c.-442T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 1,612,206 control chromosomes in the GnomAD database, including 638,460 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60318 hom., cov: 38)
  • Exomes 𝑓: 0.89 (578142 hom.)
• Consequence: TMPPE NM_001039770.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18 O:1
• Conservation: PhyloP100: 0.792
• Publications: 23 publications found

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]

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-33097052-A-G is Benign according to our data. Variant chr3-33097052-A-G is described in ClinVar as Benign. ClinVar VariationId is 92905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPPE	NM_001039770.3	c.-442T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	ENST00000342462.5	NP_001034859.2
GLB1	NM_000404.4	c.34T>C	p.Leu12Leu	synonymous_variant	Exon 1 of 16	ENST00000307363.10	NP_000395.3
TMPPE	NM_001039770.3	c.-442T>C		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
TMPPE	ENST00000342462.5	c.-442T>C		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2	2	NM_001039770.3	ENSP00000343398.4
GLB1	ENST00000307363.10	c.34T>C	p.Leu12Leu	synonymous_variant	Exon 1 of 16	1	NM_000404.4	ENSP00000306920.4
TMPPE	ENST00000342462.5	c.-442T>C		5_prime_UTR_variant	Exon 1 of 2	2	NM_001039770.3	ENSP00000343398.4

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135240 AN: 152122 Hom.: 60287 Cov.: 38

Gnomad AFR AF: 0.866

Gnomad AMI AF: 0.921

Gnomad AMR AF: 0.944

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.949

Gnomad FIN AF: 0.873

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.879

Gnomad OTH AF: 0.906

GnomAD2 exomes AF: 0.909 AC: 222982 AN: 245356 AF XY: 0.910

Gnomad AFR exome AF: 0.866

Gnomad AMR exome AF: 0.959

Gnomad ASJ exome AF: 0.913

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.871

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.908

GnomAD4 exome AF: 0.889 AC: 1298544 AN: 1459976 Hom.: 578142 Cov.: 94 AF XY: 0.891 AC XY: 647051 AN XY: 726342

African (AFR) AF: 0.862 AC: 28725 AN: 33338

American (AMR) AF: 0.956 AC: 42601 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 23732 AN: 26046

East Asian (EAS) AF: 1.00 AC: 39590 AN: 39602

South Asian (SAS) AF: 0.952 AC: 81898 AN: 86052

European-Finnish (FIN) AF: 0.871 AC: 46496 AN: 53382

Middle Eastern (MID) AF: 0.959 AC: 5522 AN: 5758

European-Non Finnish (NFE) AF: 0.879 AC: 975989 AN: 1110934

Other (OTH) AF: 0.895 AC: 53991 AN: 60310

GnomAD4 genome AF: 0.889 AC: 135320 AN: 152230 Hom.: 60318 Cov.: 38 AF XY: 0.892 AC XY: 66418 AN XY: 74424

African (AFR) AF: 0.865 AC: 35961 AN: 41566

American (AMR) AF: 0.944 AC: 14439 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3151 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5167 AN: 5170

South Asian (SAS) AF: 0.949 AC: 4586 AN: 4834

European-Finnish (FIN) AF: 0.873 AC: 9263 AN: 10610

Middle Eastern (MID) AF: 0.959 AC: 280 AN: 292

European-Non Finnish (NFE) AF: 0.879 AC: 59715 AN: 67962

Other (OTH) AF: 0.907 AC: 1918 AN: 2114

Alfa AF: 0.882 Hom.: 32048

Bravo AF: 0.894

Asia WGS AF: 0.968 AC: 3360 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

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

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

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mucopolysaccharidosis, MPS-IV-B Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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

not provided Benign:3

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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 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.

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.65
PhyloP100		0.79
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	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: rs7614776; hg19: chr3-33138544; COSMIC: COSV56561114; COSMIC: COSV56561114;