18-657352-T-C

Variant names:

• chr18-657352-T-C
• rs2853741
• ENST00000323813.6:n.511+490A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000701410.1(TYMSOS):​n.245A>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 0.684 in 173,424 control chromosomes in the GnomAD database, including 40,665 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 0.68 (34942 hom., cov: 31)
  • Exomes 𝑓: 0.73 (5723 hom.)
• Consequence: TYMSOS ENST00000701410.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.883
• Publications: 30 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000701410.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMSOS	NR_171001.1		n.450+490A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMSOS	ENST00000323813.6	TSL:1	n.511+490A>G		intron	N/A
	TYMSOS	ENST00000701410.1		n.245A>G		non_coding_transcript_exon	Exon 1 of 2
	TYMSOS	ENST00000585033.1	TSL:2	n.428+490A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102856 AN: 151908 Hom.: 34908 Cov.: 31

Gnomad AFR AF: 0.631

Gnomad AMI AF: 0.790

Gnomad AMR AF: 0.726

Gnomad ASJ AF: 0.694

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.635

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.676

GnomAD4 exome AF: 0.729 AC: 15596 AN: 21396 Hom.: 5723 AF XY: 0.730 AC XY: 7923 AN XY: 10848

African (AFR) AF: 0.659 AC: 511 AN: 776

American (AMR) AF: 0.759 AC: 419 AN: 552

Ashkenazi Jewish (ASJ) AF: 0.757 AC: 689 AN: 910

East Asian (EAS) AF: 0.509 AC: 510 AN: 1002

South Asian (SAS) AF: 0.741 AC: 160 AN: 216

European-Finnish (FIN) AF: 0.780 AC: 1367 AN: 1752

Middle Eastern (MID) AF: 0.725 AC: 87 AN: 120

European-Non Finnish (NFE) AF: 0.739 AC: 10761 AN: 14564

Other (OTH) AF: 0.726 AC: 1092 AN: 1504

GnomAD4 genome AF: 0.677 AC: 102945 AN: 152028 Hom.: 34942 Cov.: 31 AF XY: 0.679 AC XY: 50431 AN XY: 74310

African (AFR) AF: 0.631 AC: 26168 AN: 41450

American (AMR) AF: 0.726 AC: 11093 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2408 AN: 3472

East Asian (EAS) AF: 0.475 AC: 2443 AN: 5148

South Asian (SAS) AF: 0.635 AC: 3059 AN: 4820

European-Finnish (FIN) AF: 0.731 AC: 7734 AN: 10576

Middle Eastern (MID) AF: 0.633 AC: 186 AN: 294

European-Non Finnish (NFE) AF: 0.702 AC: 47717 AN: 67960

Other (OTH) AF: 0.671 AC: 1418 AN: 2114

Alfa AF: 0.687 Hom.: 126463

Bravo AF: 0.673

Asia WGS AF: 0.544 AC: 1891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.0
DANN	Benign	0.59
PhyloP100		0.88
PromoterAI		0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2853741; hg19: chr18-657352;