chr18-659236-C-T

Variant names:

• chr18-659236-C-T
• rs502396
• NM_001071.4:c.206-405C>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.206-405C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 152,050 control chromosomes in the GnomAD database, including 17,134 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 0.46 (17134 hom., cov: 32)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60
• Publications: 28 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.556 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMS	NM_001071.4	MANE Select	c.206-405C>T		intron	N/A	NP_001062.1	Q53Y97
	TYMS	NM_001354867.2		c.206-405C>T		intron	N/A	NP_001341796.1	P04818-2
	TYMS	NM_001354868.2		c.205+1289C>T		intron	N/A	NP_001341797.1	P04818-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMS	ENST00000323274.15	TSL:1 MANE Select	c.206-405C>T		intron	N/A	ENSP00000315644.10	P04818-1
	TYMS	ENST00000323224.7	TSL:1	c.206-405C>T		intron	N/A	ENSP00000314727.7	P04818-2
	TYMS	ENST00000323250.9	TSL:1	c.205+1289C>T		intron	N/A	ENSP00000314902.5	P04818-3

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70220 AN: 151932 Hom.: 17109 Cov.: 32

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.529

Gnomad OTH AF: 0.459

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.462 AC: 70284 AN: 152050 Hom.: 17134 Cov.: 32 AF XY: 0.462 AC XY: 34342 AN XY: 74324

African (AFR) AF: 0.310 AC: 12868 AN: 41484

American (AMR) AF: 0.566 AC: 8648 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1716 AN: 3472

East Asian (EAS) AF: 0.277 AC: 1432 AN: 5164

South Asian (SAS) AF: 0.465 AC: 2239 AN: 4810

European-Finnish (FIN) AF: 0.543 AC: 5739 AN: 10572

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.529 AC: 35971 AN: 67954

Other (OTH) AF: 0.456 AC: 965 AN: 2114

Alfa AF: 0.499 Hom.: 50791

Bravo AF: 0.456

Asia WGS AF: 0.363 AC: 1262 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.077
DANN	Benign	0.71
PhyloP100		-1.6
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: rs502396; hg19: chr18-659236; COSMIC: COSV60076323; COSMIC: COSV60076323;