dbSNP rs2853742: TYMSOS:n.511+368A>G (chr18-657474-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 ENST00000323813.6(TYMSOS):n.511+368A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 272,772 control chromosomes in the GnomAD database, including 10,597 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 0.26 ( 5395 hom., cov: 31)

Exomes 𝑓: 0.29 ( 5202 hom. )

Consequence

TYMSOS
ENST00000323813.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.53

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=-0.82).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TYMSOS	NR_171001.1 link	n.450+368A>G	intron_variant	Intron 1 of 1
TYMS	NM_001071.4 link	c.-269T>C	upstream_gene_variant		ENST00000323274.15	NP_001062.1	P04818-1Q53Y97
TYMS	NM_001354867.2 link	c.-269T>C	upstream_gene_variant			NP_001341796.1
TYMS	NM_001354868.2 link	c.-269T>C	upstream_gene_variant			NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15 link	c.-269T>C		upstream_gene_variant		1	NM_001071.4	ENSP00000315644.10		P04818-1

Frequencies

GnomAD3 genomes

AF:

0.264

AC:

40114

AN:

151900

Hom.:

5393

Cov.:

show subpopulations

Gnomad AFR

AF:

0.236

Gnomad AMI

AF:

0.216

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.143

Gnomad SAS

AF:

0.253

Gnomad FIN

AF:

0.362

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.257

GnomAD4 exome

AF:

0.289

AC:

34839

AN:

120754

Hom.:

5202

AF XY:

0.289

AC XY:

17937

AN XY:

62038

show subpopulations

African (AFR)

AF:

0.241

AC:

757

AN:

3142

American (AMR)

AF:

0.300

AC:

1009

AN:

3364

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1286

AN:

4336

East Asian (EAS)

AF:

0.179

AC:

1559

AN:

8710

South Asian (SAS)

AF:

0.279

AC:

321

AN:

1150

European-Finnish (FIN)

AF:

0.375

AC:

4401

AN:

11730

Middle Eastern (MID)

AF:

0.189

AC:

122

AN:

644

European-Non Finnish (NFE)

AF:

0.291

AC:

23251

AN:

79906

Other (OTH)

AF:

0.274

AC:

2133

AN:

7772

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

1128

2255

3383

4510

5638

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.264

AC:

40141

AN:

152018

Hom.:

5395

Cov.:

AF XY:

0.267

AC XY:

19833

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.236

AC:

9792

AN:

41484

American (AMR)

AF:

0.264

AC:

4032

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

967

AN:

3466

East Asian (EAS)

AF:

0.143

AC:

736

AN:

5140

South Asian (SAS)

AF:

0.253

AC:

1218

AN:

4810

European-Finnish (FIN)

AF:

0.362

AC:

3832

AN:

10578

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.276

AC:

18767

AN:

67940

Other (OTH)

AF:

0.256

AC:

541

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1525

3050

4576

6101

7626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.273

Hom.:

1270

Bravo

AF:

0.258

Asia WGS

AF:

0.184

AC:

642

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

8.3

(source)

DANN

Benign

0.65

PhyloP100

1.5

PromoterAI

-0.0059

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

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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rs2853742

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over