rs2853539

Variant names:

• chr18-659829-A-G
• rs2853539
• NM_001071.4:c.279+115A>G

Your query was ambiguous. Multiple possible variants found:

• chr18-659829-A-G
• chr18-659829-A-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 9 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMS	NM_001071.4	MANE Select	c.279+115A>G		intron	N/A	NP_001062.1
	TYMS	NM_001354867.2		c.279+115A>G		intron	N/A	NP_001341796.1
	TYMS	NM_001354868.2		c.205+1882A>G		intron	N/A	NP_001341797.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMS	ENST00000323274.15	TSL:1 MANE Select	c.279+115A>G		intron	N/A	ENSP00000315644.10
	TYMS	ENST00000323224.7	TSL:1	c.279+115A>G		intron	N/A	ENSP00000314727.7
	TYMS	ENST00000323250.9	TSL:1	c.205+1882A>G		intron	N/A	ENSP00000314902.5

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

African (AFR) AF: 0.794 AC: 15185 AN: 19134

American (AMR) AF: 0.395 AC: 15045 AN: 38104

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 9194 AN: 19310

East Asian (EAS) AF: 0.663 AC: 23925 AN: 36110

South Asian (SAS) AF: 0.546 AC: 35513 AN: 65006

European-Finnish (FIN) AF: 0.456 AC: 21141 AN: 46376

Middle Eastern (MID) AF: 0.575 AC: 1837 AN: 3194

European-Non Finnish (NFE) AF: 0.462 AC: 218314 AN: 472188

Other (OTH) AF: 0.511 AC: 18397 AN: 36012

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

African (AFR) AF: 0.783 AC: 32484 AN: 41474

American (AMR) AF: 0.430 AC: 6564 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1685 AN: 3470

East Asian (EAS) AF: 0.683 AC: 3515 AN: 5148

South Asian (SAS) AF: 0.550 AC: 2651 AN: 4822

European-Finnish (FIN) AF: 0.451 AC: 4750 AN: 10542

Middle Eastern (MID) AF: 0.614 AC: 178 AN: 290

European-Non Finnish (NFE) AF: 0.460 AC: 31288 AN: 67950

Other (OTH) AF: 0.549 AC: 1158 AN: 2110

Alfa AF: 0.280 Hom.: 2304

Bravo AF: 0.565

Asia WGS AF: 0.630 AC: 2195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.48
PhyloP100		0.063
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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