chr18-668465-C-T

Variant names:

• chr18-668465-C-T
• rs16948305
• NM_001071.4:c.455-607C>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.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
• Publications: 8 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]

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]

ACMG classification

Our verdict: Benign. The variant received -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.

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.455-607C>T		intron	N/A	NP_001062.1	Q53Y97
	TYMS	NM_001354867.2		c.455-2227C>T		intron	N/A	NP_001341796.1	P04818-2
	TYMS	NM_001354868.2		c.206-607C>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.455-607C>T		intron	N/A	ENSP00000315644.10	P04818-1
	TYMS	ENST00000323224.7	TSL:1	c.455-2227C>T		intron	N/A	ENSP00000314727.7	P04818-2
	TYMS	ENST00000323250.9	TSL:1	c.206-607C>T		intron	N/A	ENSP00000314902.5	P04818-3

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

African (AFR) AF: 0.119 AC: 4944 AN: 41486

American (AMR) AF: 0.0849 AC: 1298 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 353 AN: 3470

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5184

South Asian (SAS) AF: 0.0863 AC: 416 AN: 4820

European-Finnish (FIN) AF: 0.146 AC: 1547 AN: 10578

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10068 AN: 67988

Other (OTH) AF: 0.125 AC: 265 AN: 2114

Alfa AF: 0.129 Hom.: 689

Bravo AF: 0.121

Asia WGS AF: 0.0510 AC: 176 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.61
DANN	Benign	0.74
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: rs16948305; hg19: chr18-668465;