18-657785-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001071.4(TYMS):c.43C>T(p.Pro15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,452,330 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P15T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 41 hom. )

Consequence

TYMS
NM_001071.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.0740

Publications

4 publications found

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:

TYMSOS (HGNC:29553): (TYMS opposite strand RNA)

TYMSOS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034260154).

BP6

Variant 18-657785-C-T is Benign according to our data. Variant chr18-657785-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3055385.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 41 Digenic gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001071.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYMS	NM_001071.4	MANE Select	c.43C>T	p.Pro15Ser	missense	Exon 1 of 7	NP_001062.1	Q53Y97
TYMS	NM_001354867.2		c.43C>T	p.Pro15Ser	missense	Exon 1 of 6	NP_001341796.1	P04818-2
TYMS	NM_001354868.2		c.43C>T	p.Pro15Ser	missense	Exon 1 of 5	NP_001341797.1	P04818-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TYMS	ENST00000323274.15	TSL:1 MANE Select	c.43C>T	p.Pro15Ser	missense	Exon 1 of 7	ENSP00000315644.10	P04818-1
TYMS	ENST00000323224.7	TSL:1	c.43C>T	p.Pro15Ser	missense	Exon 1 of 6	ENSP00000314727.7	P04818-2
TYMS	ENST00000323250.9	TSL:1	c.43C>T	p.Pro15Ser	missense	Exon 1 of 5	ENSP00000314902.5	P04818-3

Frequencies

GnomAD3 genomes

AF:

0.00386

AC:

587

AN:

151964

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00440

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000851

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00590

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00424

AC:

217

AN:

51128

AF XY:

0.00453

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.0214

Gnomad EAS exome

AF:

0.000720

Gnomad FIN exome

AF:

0.00140

Gnomad NFE exome

AF:

0.00596

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00557

AC:

7243

AN:

1300256

Hom.:

Cov.:

AF XY:

0.00549

AC XY:

3506

AN XY:

638576

show subpopulations

African (AFR)

AF:

0.000788

AC:

AN:

25380

American (AMR)

AF:

0.00254

AC:

AN:

20084

Ashkenazi Jewish (ASJ)

AF:

0.0218

AC:

455

AN:

20826

East Asian (EAS)

AF:

0.0000704

AC:

AN:

28412

South Asian (SAS)

AF:

0.000440

AC:

AN:

65858

European-Finnish (FIN)

AF:

0.000837

AC:

AN:

39446

Middle Eastern (MID)

AF:

0.00315

AC:

AN:

5074

European-Non Finnish (NFE)

AF:

0.00607

AC:

6316

AN:

1041350

Other (OTH)

AF:

0.00596

AC:

321

AN:

53826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

447

895

1342

1790

2237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

254

508

762

1016

1270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00386

AC:

587

AN:

152074

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

278

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00133

AC:

AN:

41486

American (AMR)

AF:

0.00288

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0193

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000851

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00590

AC:

401

AN:

67956

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00390

Hom.:

Bravo

AF:

0.00406

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00187

AC:

ExAC

AF:

0.00211

AC:

195

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

TYMS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

6.8

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.17

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

PhyloP100

0.074

PrimateAI

Uncertain

0.76

PROVEAN

Benign

0.010

REVEL

Benign

0.022

Sift

Benign

0.24

Sift4G

Benign

0.20

Polyphen

0.049

Vest4

0.22

MVP

0.068

MPC

0.88

ClinPred

0.014

GERP RS

-2.6

PromoterAI

0.15

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.9

Varity_R

0.057

gMVP

0.19

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over