chr18-669101-CAA-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001071.4(TYMS):c.486_487del(p.Arg163SerfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000342 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
TYMS
NM_001071.4 frameshift
NM_001071.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.06
Genes affected
TYMS (HGNC:12441): (thymidylate synthetase) Thymidylate synthase catalyzes the methylation of deoxyuridylate to deoxythymidylate using, 10-methylenetetrahydrofolate (methylene-THF) as a cofactor. This function maintains the dTMP (thymidine-5-prime monophosphate) pool critical for DNA replication and repair. The enzyme has been of interest as a target for cancer chemotherapeutic agents. It is considered to be the primary site of action for 5-fluorouracil, 5-fluoro-2-prime-deoxyuridine, and some folate analogs. Expression of this gene and that of a naturally occurring antisense transcript, mitochondrial enolase superfamily member 1 (GeneID:55556), vary inversely when cell-growth progresses from late-log to plateau phase. Polymorphisms in this gene may be associated with etiology of neoplasia, including breast cancer, and response to chemotherapy. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 18-669101-CAA-C is Pathogenic according to our data. Variant chr18-669101-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 1693537.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-669101-CAA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TYMS | NM_001071.4 | c.486_487del | p.Arg163SerfsTer3 | frameshift_variant | 4/7 | ENST00000323274.15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TYMS | ENST00000323274.15 | c.486_487del | p.Arg163SerfsTer3 | frameshift_variant | 4/7 | 1 | NM_001071.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461840Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727224
GnomAD4 exome
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2
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727224
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Dyskeratosis congenita, digenic Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 22, 2022 | - - |
Dyskeratosis congenita Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Bone Marrow Failure laboratory, Queen Mary University London | Jun 22, 2022 | This heterozygous frameshift variant of TYMS was identified in dyskeratosis congenita. The following ACMG/AMP criteria were used: PVS1, PS4_supporting, PM2_supporting, PP3 - |
Computational scores
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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
Publications
No publications associated with this variant yet.