11-74239225-T-C
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_016147.3(PPME1):āc.803T>Cā(p.Ile268Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,613,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000085 ( 0 hom., cov: 31)
Exomes š: 0.000096 ( 0 hom. )
Consequence
PPME1
NM_016147.3 missense
NM_016147.3 missense
Scores
2
17
Clinical Significance
Conservation
PhyloP100: 3.67
Genes affected
PPME1 (HGNC:30178): (protein phosphatase methylesterase 1) This gene encodes a protein phosphatase methylesterase localized to the nucleus. The encoded protein acts on the protein phosphatase-2A catalytic subunit and supports the ERK pathway through dephosphorylation of regulatory proteins. It plays a role in malignant glioma progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]
P4HA3 (HGNC:30135): (prolyl 4-hydroxylase subunit alpha 3) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.013070762).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPME1 | NM_016147.3 | c.803T>C | p.Ile268Thr | missense_variant | 9/14 | ENST00000328257.13 | |
PPME1 | NM_001271593.2 | c.803T>C | p.Ile268Thr | missense_variant | 9/14 | ||
PPME1 | XM_047427116.1 | c.803T>C | p.Ile268Thr | missense_variant | 9/12 | ||
PPME1 | XM_017017913.3 | c.803T>C | p.Ile268Thr | missense_variant | 9/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPME1 | ENST00000328257.13 | c.803T>C | p.Ile268Thr | missense_variant | 9/14 | 1 | NM_016147.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152136Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000157 AC: 39AN: 248374Hom.: 0 AF XY: 0.000141 AC XY: 19AN XY: 134742
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GnomAD4 exome AF: 0.0000958 AC: 140AN: 1461138Hom.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73AN XY: 726846
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GnomAD4 genome AF: 0.0000854 AC: 13AN: 152136Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7AN XY: 74318
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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.803T>C (p.I268T) alteration is located in exon 9 (coding exon 9) of the PPME1 gene. This alteration results from a T to C substitution at nucleotide position 803, causing the isoleucine (I) at amino acid position 268 to be replaced by a threonine (T). 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
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;T
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N
MutationTaster
Benign
D;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
B;.
Vest4
MVP
MPC
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