rs2853742

Variant names:

• chr18-657474-T-C
• rs2853742
• ENST00000323813.5:n.509+368A>G

Variant summary

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

The ENST00000688642.2(TYMSOS):​n.124A>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 0.275 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 ENST00000688642.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.53

Genes affected

TYMSOS (HGNC:29553): (TYMS opposite strand RNA)

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]

ENSG00000263727 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMSOS	NR_171001.1	n.450+368A>G		intron_variant	Intron 1 of 1
TYMS	NM_001071.4	c.-269T>C		upstream_gene_variant		ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2	c.-269T>C		upstream_gene_variant			NP_001341796.1
TYMS	NM_001354868.2	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	c.-269T>C		upstream_gene_variant		1	NM_001071.4	ENSP00000315644.10

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40114 AN: 151900 Hom.: 5393 Cov.: 31

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

Gnomad4 AFR exome AF: 0.241

Gnomad4 AMR exome AF: 0.300

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.179

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.291

Gnomad4 OTH exome AF: 0.274

GnomAD4 genome AF: 0.264 AC: 40141 AN: 152018 Hom.: 5395 Cov.: 31 AF XY: 0.267 AC XY: 19833 AN XY: 74298

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.264

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.143

Gnomad4 SAS AF: 0.253

Gnomad4 FIN AF: 0.362

Gnomad4 NFE AF: 0.276

Gnomad4 OTH AF: 0.256

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
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2853742; hg19: chr18-657474;