rs1064792859
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001953.5(TYMP):c.228G>A(p.Met76Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,972 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 (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
TYMP
NM_001953.5 missense
NM_001953.5 missense
Scores
7
9
2
Clinical Significance
Conservation
PhyloP100: 5.58
Genes affected
TYMP (HGNC:3148): (thymidine phosphorylase) This gene encodes an angiogenic factor which promotes angiogenesis in vivo and stimulates the in vitro growth of a variety of endothelial cells. It has a highly restricted target cell specificity acting only on endothelial cells. Mutations in this gene have been associated with mitochondrial neurogastrointestinal encephalomyopathy. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.981
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYMP | NM_001953.5 | c.228G>A | p.Met76Ile | missense_variant | 3/10 | ENST00000252029.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYMP | ENST00000252029.8 | c.228G>A | p.Met76Ile | missense_variant | 3/10 | 1 | NM_001953.5 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249660Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135458
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460972Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726820
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GnomAD4 genome ? Cov.: 33
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33
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial DNA depletion syndrome 1 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 29, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | GeneReviews | Jan 14, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2023 | Variant summary: TYMP c.228G>A (p.Met76Ile) results in a conservative amino acid change located in the Glycosyl transferase family 3, N-terminal domain (IPR017459) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249660 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.228G>A has been reported in the literature in individuals affected with Mitochondrial DNA Depletion Syndrome 1 (MNGIE type) (Martin_2004). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 15505189). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
D;.;D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0932);Loss of MoRF binding (P = 0.0932);Loss of MoRF binding (P = 0.0932);Loss of MoRF binding (P = 0.0932);Loss of MoRF binding (P = 0.0932);
MVP
MPC
1.3
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