rs7614776

Positions:

• chr3-33097052-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 92905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-33097052-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TMPPE	NM_001039770.3	c.-442T>C		5_prime_UTR_premature_start_codon_gain_variant	1/2	ENST00000342462.5	NP_001034859.2
GLB1	NM_000404.4	c.34T>C	p.Leu12Leu	synonymous_variant	1/16	ENST00000307363.10	NP_000395.3
TMPPE	NM_001039770.3	c.-442T>C		5_prime_UTR_variant	1/2	ENST00000342462.5	NP_001034859.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPPE	ENST00000342462.5	c.-442T>C		5_prime_UTR_premature_start_codon_gain_variant	1/2	2	NM_001039770.3	ENSP00000343398.4
GLB1	ENST00000307363.10	c.34T>C	p.Leu12Leu	synonymous_variant	1/16	1	NM_000404.4	ENSP00000306920.4
TMPPE	ENST00000342462.5	c.-442T>C		5_prime_UTR_variant	1/2	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

GnomAD3 exomes AF: 0.909 AC: 222982 AN: 245356 Hom.: 101581 AF XY: 0.910 AC XY: 121644 AN XY: 133648

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 SAS exome AF: 0.954

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

Gnomad4 AFR exome AF: 0.862

Gnomad4 AMR exome AF: 0.956

Gnomad4 ASJ exome AF: 0.911

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.952

Gnomad4 FIN exome AF: 0.871

Gnomad4 NFE exome AF: 0.879

Gnomad4 OTH exome AF: 0.895

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

Gnomad4 AFR AF: 0.865

Gnomad4 AMR AF: 0.944

Gnomad4 ASJ AF: 0.908

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.949

Gnomad4 FIN AF: 0.873

Gnomad4 NFE AF: 0.879

Gnomad4 OTH AF: 0.907

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Mucopolysaccharidosis, MPS-IV-B Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 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. -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Infantile GM1 gangliosidosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

GM1 gangliosidosis Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - GM1	-	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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

GM1 gangliosidosis type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.5
DANN	Benign	0.65
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

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

Other links and lift over

dbSNP: rs7614776; hg19: chr3-33138544; COSMIC: COSV56561114; COSMIC: COSV56561114;