Genetic Variant TYMSOS:n.511+490A>G (chr18-657352-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000701410.1(TYMSOS):n.245A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 173,424 control chromosomes in the GnomAD database, including 40,665 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.68 ( 34942 hom., cov: 31)

Exomes 𝑓: 0.73 ( 5723 hom. )

Consequence

TYMSOS
ENST00000701410.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.883

Publications

30 publications found

Variant links:

Genes affected

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

TYMSOS links:

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:

ENSG00000263727 (HGNC:):

ENSG00000263727 links:

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new If you want to explore the variant's impact on the transcript ENST00000701410.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000701410.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMSOS	NR_171001.1		n.450+490A>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
TYMSOS	ENST00000323813.6	TSL:1	n.511+490A>G	intron	N/A
TYMSOS	ENST00000701410.1		n.245A>G	non_coding_transcript_exon	Exon 1 of 2
TYMSOS	ENST00000585033.1	TSL:2	n.428+490A>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.677

AC:

102856

AN:

151908

Hom.:

34908

Cov.:

show subpopulations

Gnomad AFR

AF:

0.631

Gnomad AMI

AF:

0.790

Gnomad AMR

AF:

0.726

Gnomad ASJ

AF:

0.694

Gnomad EAS

AF:

0.474

Gnomad SAS

AF:

0.635

Gnomad FIN

AF:

0.731

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.702

Gnomad OTH

AF:

0.676

GnomAD4 exome

AF:

0.729

AC:

15596

AN:

21396

Hom.:

5723

AF XY:

0.730

AC XY:

7923

AN XY:

10848

show subpopulations

African (AFR)

AF:

0.659

AC:

511

AN:

776

American (AMR)

AF:

0.759

AC:

419

AN:

552

Ashkenazi Jewish (ASJ)

AF:

0.757

AC:

689

AN:

910

East Asian (EAS)

AF:

0.509

AC:

510

AN:

1002

South Asian (SAS)

AF:

0.741

AC:

160

AN:

216

European-Finnish (FIN)

AF:

0.780

AC:

1367

AN:

1752

Middle Eastern (MID)

AF:

0.725

AC:

AN:

120

European-Non Finnish (NFE)

AF:

0.739

AC:

10761

AN:

14564

Other (OTH)

AF:

0.726

AC:

1092

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

208

416

624

832

1040

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

204

272

340

<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:

0.677

AC:

102945

AN:

152028

Hom.:

34942

Cov.:

AF XY:

0.679

AC XY:

50431

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.631

AC:

26168

AN:

41450

American (AMR)

AF:

0.726

AC:

11093

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.694

AC:

2408

AN:

3472

East Asian (EAS)

AF:

0.475

AC:

2443

AN:

5148

South Asian (SAS)

AF:

0.635

AC:

3059

AN:

4820

European-Finnish (FIN)

AF:

0.731

AC:

7734

AN:

10576

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.702

AC:

47717

AN:

67960

Other (OTH)

AF:

0.671

AC:

1418

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1722

3444

5165

6887

8609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

812

1624

2436

3248

4060

<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:

0.687

Hom.:

126463

Bravo

AF:

0.673

Asia WGS

AF:

0.544

AC:

1891

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

8.0

(source)

DANN

Benign

0.59

PhyloP100

0.88

PromoterAI

0.016

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

0.97

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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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