3-33093113-G-T

Position:

• chr3-33093113-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000307363.10(GLB1):​c.75+3898C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLB1 ENST00000307363.10 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.682

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08033064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPPE	NM_001039770.3	c.1083C>A	p.Asp361Glu	missense_variant	2/2	ENST00000342462.5	NP_001034859.2
GLB1	NM_000404.4	c.75+3898C>A		intron_variant		ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPPE	ENST00000342462.5	c.1083C>A	p.Asp361Glu	missense_variant	2/2	2	NM_001039770.3	ENSP00000343398	P1
GLB1	ENST00000307363.10	c.75+3898C>A		intron_variant		1	NM_000404.4	ENSP00000306920	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.1083C>A (p.D361E) alteration is located in exon 2 (coding exon 1) of the TMPPE gene. This alteration results from a C to A substitution at nucleotide position 1083, causing the aspartic acid (D) at amino acid position 361 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.94
DEOGEN2	Benign	0.21	.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.48	.;N
MutationTaster	Benign	1.0	D;D;D;D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.14
Sift	Benign	0.35	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0010	.;B
Vest4		0.062
MutPred		0.34		.;Loss of sheet (P = 0.1398);
MVP		0.20
MPC		0.31
ClinPred		0.18	T
GERP RS		3.0
Varity_R		0.063
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-33134605;