3-33093955-A-G
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001039770.3(TMPPE):āc.241T>Cā(p.Cys81Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
TMPPE
NM_001039770.3 missense
NM_001039770.3 missense
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 4.59
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 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.82
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMPPE | NM_001039770.3 | c.241T>C | p.Cys81Arg | missense_variant | 2/2 | ENST00000342462.5 | |
GLB1 | NM_000404.4 | c.75+3056T>C | intron_variant | ENST00000307363.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMPPE | ENST00000342462.5 | c.241T>C | p.Cys81Arg | missense_variant | 2/2 | 2 | NM_001039770.3 | P1 | |
GLB1 | ENST00000307363.10 | c.75+3056T>C | intron_variant | 1 | NM_000404.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 247938Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134494
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461824Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727214
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152256Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74394
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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 | Feb 23, 2023 | The c.241T>C (p.C81R) alteration is located in exon 2 (coding exon 1) of the TMPPE gene. This alteration results from a T to C substitution at nucleotide position 241, causing the cysteine (C) at amino acid position 81 to be replaced by an arginine (R). 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
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Gain of disorder (P = 0.0165);
MVP
MPC
ClinPred
D
GERP RS
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