rs2853539

Positions:

• chr18-659829-A-G
• chr18-659829-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001071.4(TYMS):​c.279+115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 887,410 control chromosomes in the GnomAD database, including 115,663 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 0.56 (25160 hom., cov: 32)
  • Exomes 𝑓: 0.49 (90503 hom.)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0630

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMS	NM_001071.4	c.279+115A>G		intron_variant		ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2	c.279+115A>G		intron_variant			NP_001341796.1
TYMS	NM_001354868.2	c.205+1882A>G		intron_variant			NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.279+115A>G		intron_variant		1	NM_001071.4	ENSP00000315644.10
TYMS	ENST00000323224.7	c.279+115A>G		intron_variant		1		ENSP00000314727.7
TYMS	ENST00000323250.9	c.205+1882A>G		intron_variant		1		ENSP00000314902.5
TYMS	ENST00000579128.1	n.357+115A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.556 AC: 84487 AN: 151860 Hom.: 25116 Cov.: 32

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.329

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.451

Gnomad MID AF: 0.619

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.548

GnomAD4 exome AF: 0.488 AC: 358551 AN: 735434 Hom.: 90503 AF XY: 0.490 AC XY: 190477 AN XY: 389004

Gnomad4 AFR exome AF: 0.794

Gnomad4 AMR exome AF: 0.395

Gnomad4 ASJ exome AF: 0.476

Gnomad4 EAS exome AF: 0.663

Gnomad4 SAS exome AF: 0.546

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.462

Gnomad4 OTH exome AF: 0.511

GnomAD4 genome AF: 0.556 AC: 84570 AN: 151976 Hom.: 25160 Cov.: 32 AF XY: 0.556 AC XY: 41281 AN XY: 74286

Gnomad4 AFR AF: 0.783

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.683

Gnomad4 SAS AF: 0.550

Gnomad4 FIN AF: 0.451

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.549

Alfa AF: 0.475 Hom.: 2304

Bravo AF: 0.565

Asia WGS AF: 0.630 AC: 2195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.48

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

LitVar

Other links and lift over

dbSNP: rs2853539; hg19: chr18-659829; COSMIC: COSV60074508; COSMIC: COSV60074508;