rs16948305

Positions:

• chr18-668465-C-T

Variant summary

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

The NM_001071.4(TYMS):​c.455-607C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 152,128 control chromosomes in the GnomAD database, including 1,284 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 0.13 (1284 hom., cov: 32)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65

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]

ENOSF1 (HGNC:30365): (enolase superfamily member 1) This gene can encode a mitochondrial enzyme that is thought to convert L-fuconate to 2-keto-3-deoxy-L-fuconate. This locus was originally identified as the source of antisense RNAs of the adjacent thymidylate synthase gene. Splice variants at this locus may contain an alternate 3' exon that is complementary to the 3'UTR and terminal intron of the thymidylate synthase (TS) RNA and may downregulate TS expression. [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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMS	NM_001071.4	c.455-607C>T		intron_variant		ENST00000323274.15	NP_001062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.455-607C>T		intron_variant		1	NM_001071.4	ENSP00000315644.10

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19082 AN: 152010 Hom.: 1280 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.0852

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.0858

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.126 AC: 19104 AN: 152128 Hom.: 1284 Cov.: 32 AF XY: 0.122 AC XY: 9107 AN XY: 74384

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.0849

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.00502

Gnomad4 SAS AF: 0.0863

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.148

Gnomad4 OTH AF: 0.125

Alfa AF: 0.135 Hom.: 383

Bravo AF: 0.121

Asia WGS AF: 0.0510 AC: 176 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.61
DANN	Benign	0.74

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: rs16948305; hg19: chr18-668465;