Variant 18-662209-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001071.4(TYMS):c.343C>T(p.Arg115Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000616 in 1,461,636 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

TYMS
NM_001071.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 3.79

Variant links:

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]

TYMS links:

Genome browser will be placed here

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 18-662209-C-T is Pathogenic according to our data. Variant chr18-662209-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1693535.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-662209-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TYMS	NM_001071.4 linkuse as main transcript	c.343C>T	p.Arg115Ter	stop_gained	3/7	ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2 linkuse as main transcript	c.343C>T	p.Arg115Ter	stop_gained	3/6		NP_001341796.1
TYMS	NM_001354868.2 linkuse as main transcript	c.205+4262C>T		intron_variant			NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15 linkuse as main transcript	c.343C>T	p.Arg115Ter	stop_gained	3/7	1	NM_001071.4	ENSP00000315644	P1	P04818-1
TYMS	ENST00000323224.7 linkuse as main transcript	c.343C>T	p.Arg115Ter	stop_gained	3/6	1		ENSP00000314727		P04818-2
TYMS	ENST00000323250.9 linkuse as main transcript	c.205+4262C>T		intron_variant		1		ENSP00000314902		P04818-3
TYMS	ENST00000579128.1 linkuse as main transcript	n.421C>T		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000370

Hom.:

Bravo

AF:

0.00000378

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 nonsense variant of TYMS was identified in a 3-year old male with dyskeratosis congenita. The following ACMG/AMP criteria were used: PVS1, PM2_supporting, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

A;A;D

Vest4

0.90

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over