18-658332-C-T

Position:

• chr18-658332-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.205+385C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.136 in 1,350,480 control chromosomes in the GnomAD database, including 18,372 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 0.18 (3720 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14652 hom.)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07

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]

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMS	NM_001071.4	c.205+385C>T		intron_variant		ENST00000323274.15
TYMS	NM_001354867.2	c.205+385C>T		intron_variant
TYMS	NM_001354868.2	c.205+385C>T		intron_variant
TYMSOS	NR_171001.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMS	ENST00000323274.15	c.205+385C>T		intron_variant		1	NM_001071.4	P1

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28106 AN: 152024 Hom.: 3712 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.0187

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.578

Gnomad SAS AF: 0.328

Gnomad FIN AF: 0.0937

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.0991

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.129 AC: 155021 AN: 1198338 Hom.: 14652 Cov.: 32 AF XY: 0.135 AC XY: 79634 AN XY: 588456

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.196

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.573

Gnomad4 SAS exome AF: 0.317

Gnomad4 FIN exome AF: 0.0958

Gnomad4 NFE exome AF: 0.0979

Gnomad4 OTH exome AF: 0.169

GnomAD4 genome AF: 0.185 AC: 28138 AN: 152142 Hom.: 3720 Cov.: 33 AF XY: 0.189 AC XY: 14079 AN XY: 74378

Gnomad4 AFR AF: 0.292

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.183

Gnomad4 EAS AF: 0.577

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.0937

Gnomad4 NFE AF: 0.0991

Gnomad4 OTH AF: 0.193

Alfa AF: 0.126 Hom.: 873

Bravo AF: 0.198

Asia WGS AF: 0.425 AC: 1474 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.2
DANN	Benign	0.88

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: rs72634355; hg19: chr18-658332; COSMIC: COSV60076222; COSMIC: COSV60076222;