Genetic Variant TYMSOS:n.511+399T>G (chr18-657443-A-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.154T>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 0.665 in 151,974 control chromosomes in the GnomAD database, including 34,158 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 0.67 ( 34158 hom., cov: 30)

Consequence

TYMSOS
ENST00000701410.1 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.655

Publications

7 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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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=-0.89).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.716 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TYMSOS	NR_171001.1		n.450+399T>G	intron	N/A
TYMS	NM_001071.4	MANE Select	c.-300A>C	upstream_gene	N/A	NP_001062.1	Q53Y97
TYMS	NM_001354867.2		c.-300A>C	upstream_gene	N/A	NP_001341796.1	P04818-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank
TYMSOS	ENST00000323813.6	TSL:1	n.511+399T>G	intron	N/A
TYMSOS	ENST00000701410.1		n.154T>G	non_coding_transcript_exon	Exon 1 of 2
TYMSOS	ENST00000585033.1	TSL:2	n.428+399T>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.665

AC:

101030

AN:

151856

Hom.:

34123

Cov.:

show subpopulations

Gnomad AFR

AF:

0.543

Gnomad AMI

AF:

0.786

Gnomad AMR

AF:

0.726

Gnomad ASJ

AF:

0.724

Gnomad EAS

AF:

0.519

Gnomad SAS

AF:

0.651

Gnomad FIN

AF:

0.741

Gnomad MID

AF:

0.652

Gnomad NFE

AF:

0.721

Gnomad OTH

AF:

0.679

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.665

AC:

101115

AN:

151974

Hom.:

34158

Cov.:

AF XY:

0.668

AC XY:

49644

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.543

AC:

22523

AN:

41446

American (AMR)

AF:

0.726

AC:

11096

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.724

AC:

2512

AN:

3468

East Asian (EAS)

AF:

0.520

AC:

2670

AN:

5134

South Asian (SAS)

AF:

0.650

AC:

3125

AN:

4804

European-Finnish (FIN)

AF:

0.741

AC:

7837

AN:

10574

Middle Eastern (MID)

AF:

0.663

AC:

195

AN:

294

European-Non Finnish (NFE)

AF:

0.721

AC:

49019

AN:

67958

Other (OTH)

AF:

0.673

AC:

1421

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1701

3402

5104

6805

8506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

804

1608

2412

3216

4020

<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:

0.604

Hom.:

2482

Bravo

AF:

0.657

Asia WGS

AF:

0.579

AC:

2012

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.97

(source)

DANN

Benign

0.47

PhyloP100

-0.66

PromoterAI

-0.0016

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over