dbSNP rs2847149: TYMS:c.455-2701G>A (chr18-666371-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_001071.4(TYMS):c.455-2701G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 151,648 control chromosomes in the GnomAD database, including 24,567 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 0.55 ( 24567 hom., cov: 30)

Consequence

TYMS
NM_001071.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.902

Publications

16 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:

ENOSF1 (HGNC:30365): (enolase superfamily member 1) This gene can encode a mitochondrial enzyme that is thought to convert L-fuconate to 2-keto-3-deoxy-L-fuconate. This locus was originally identified as the source of antisense RNAs of the adjacent thymidylate synthase gene. Splice variants at this locus may contain an alternate 3' exon that is complementary to the 3'UTR and terminal intron of the thymidylate synthase (TS) RNA and may downregulate TS expression. [provided by RefSeq, Aug 2017]

ENOSF1 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=-0.88).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

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	Effect	Exon Rank	Protein
TYMS	NM_001071.4	MANE Select	c.455-2701G>A	intron	N/A	NP_001062.1
TYMS	NM_001354867.2		c.454+4051G>A	intron	N/A	NP_001341796.1
TYMS	NM_001354868.2		c.206-2701G>A	intron	N/A	NP_001341797.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TYMS	ENST00000323274.15	TSL:1 MANE Select	c.455-2701G>A	intron	N/A	ENSP00000315644.10
TYMS	ENST00000323224.7	TSL:1	c.454+4051G>A	intron	N/A	ENSP00000314727.7
TYMS	ENST00000323250.9	TSL:1	c.206-2701G>A	intron	N/A	ENSP00000314902.5

Frequencies

GnomAD3 genomes

AF:

0.550

AC:

83417

AN:

151530

Hom.:

24521

Cov.:

show subpopulations

Gnomad AFR

AF:

0.775

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.427

Gnomad ASJ

AF:

0.485

Gnomad EAS

AF:

0.684

Gnomad SAS

AF:

0.533

Gnomad FIN

AF:

0.447

Gnomad MID

AF:

0.611

Gnomad NFE

AF:

0.456

Gnomad OTH

AF:

0.542

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

GnomAD4 genome

AF:

0.551

AC:

83505

AN:

151648

Hom.:

24567

Cov.:

AF XY:

0.549

AC XY:

40706

AN XY:

74086

show subpopulations

African (AFR)

AF:

0.775

AC:

32018

AN:

41322

American (AMR)

AF:

0.427

AC:

6509

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.485

AC:

1682

AN:

3470

East Asian (EAS)

AF:

0.683

AC:

3500

AN:

5124

South Asian (SAS)

AF:

0.531

AC:

2549

AN:

4798

European-Finnish (FIN)

AF:

0.447

AC:

4710

AN:

10534

Middle Eastern (MID)

AF:

0.610

AC:

178

AN:

292

European-Non Finnish (NFE)

AF:

0.456

AC:

30905

AN:

67840

Other (OTH)

AF:

0.547

AC:

1153

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1525

3050

4575

6100

7625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

708

1416

2124

2832

3540

<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:

0.490

Hom.:

24372

Bravo

AF:

0.560

Asia WGS

AF:

0.629

AC:

2189

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.45

(source)

DANN

Benign

0.53

PhyloP100

-0.90

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

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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