22-50529325-C-T

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

Scores

7
10
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 5.58
Variant links:
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]

Genome browser will be placed here

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
TYMPNM_001953.5 linkuse as main transcriptc.228G>A p.Met76Ile missense_variant 3/10 ENST00000252029.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TYMPENST00000252029.8 linkuse as main transcriptc.228G>A p.Met76Ile missense_variant 3/101 NM_001953.5 P2P19971-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249660
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135458
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000545
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460972
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
726820
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
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 submitterclinical testingRevvity Omics, RevvityJan 29, 2020- -
Pathogenic, no assertion criteria providedliterature onlyGeneReviewsJan 14, 2016- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 16, 2023Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D;.;D;D;D
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.91
.;D;.;D;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Pathogenic
4.1
H;H;H;H;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Uncertain
-3.5
D;D;D;D;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.019
D;D;D;D;D
Sift4G
Uncertain
0.011
D;D;D;D;D
Polyphen
0.98
D;.;D;D;.
Vest4
0.69
MutPred
0.95
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
0.78
MPC
1.3
ClinPred
0.92
D
GERP RS
5.0
Varity_R
0.88
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064792859; hg19: chr22-50967754; API