chr3-33093642-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_001039770.3(TMPPE):c.554C>T(p.Ala185Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000384 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000036 ( 0 hom. )
Consequence
TMPPE
NM_001039770.3 missense
NM_001039770.3 missense
Scores
2
15
Clinical Significance
Conservation
PhyloP100: 6.05
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]
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ACMG classification
Classification made for transcript
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=0.07294735).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPPE | NM_001039770.3 | c.554C>T | p.Ala185Val | missense_variant | 2/2 | ENST00000342462.5 | |
GLB1 | NM_000404.4 | c.75+3369C>T | intron_variant | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPPE | ENST00000342462.5 | c.554C>T | p.Ala185Val | missense_variant | 2/2 | 2 | NM_001039770.3 | P1 | |
GLB1 | ENST00000307363.10 | c.75+3369C>T | intron_variant | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152140Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251152Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135746
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GnomAD4 exome AF: 0.0000363 AC: 53AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727244
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74440
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2023 | The c.554C>T (p.A185V) alteration is located in exon 2 (coding exon 1) of the TMPPE gene. This alteration results from a C to T substitution at nucleotide position 554, causing the alanine (A) at amino acid position 185 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
0.70
.;P
Vest4
MutPred
0.39
.;Loss of glycosylation at P188 (P = 0.0283);
MVP
MPC
0.42
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at