18-657685-G-C

Position:

• chr18-657685-G-C

Variant summary

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

The NM_001071.4(TYMS):​c.-58G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.44 (5506 hom., cov: 16)
  • Exomes 𝑓: 0.36 (14851 hom.)
  • Failed GnomAD Quality Control
• Consequence: TYMS NM_001071.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.372

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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMS	NM_001071.4	c.-58G>C		5_prime_UTR_variant	1/7	ENST00000323274.15
TYMSOS	NR_171001.1	n.450+157C>G		intron_variant, non_coding_transcript_variant
TYMS	NM_001354867.2	c.-58G>C		5_prime_UTR_variant	1/6
TYMS	NM_001354868.2	c.-58G>C		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMS	ENST00000323274.15	c.-58G>C		5_prime_UTR_variant	1/7	1	NM_001071.4	P1
TYMSOS	ENST00000585033.1	n.428+157C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.439 AC: 38406 AN: 87512 Hom.: 5510 Cov.: 16

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.504

Gnomad OTH AF: 0.443

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.364 AC: 130919 AN: 359768 Hom.: 14851 Cov.: 6 AF XY: 0.368 AC XY: 67406 AN XY: 183284

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.438

Gnomad4 ASJ exome AF: 0.393

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.285

Gnomad4 FIN exome AF: 0.507

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.364

GnomAD4 genome AF: 0.439 AC: 38422 AN: 87588 Hom.: 5506 Cov.: 16 AF XY: 0.440 AC XY: 18853 AN XY: 42806

Gnomad4 AFR AF: 0.261

Gnomad4 AMR AF: 0.503

Gnomad4 ASJ AF: 0.476

Gnomad4 EAS AF: 0.425

Gnomad4 SAS AF: 0.415

Gnomad4 FIN AF: 0.550

Gnomad4 NFE AF: 0.504

Gnomad4 OTH AF: 0.439

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.47
DANN	Benign	0.32
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs2853542; hg19: chr18-657685; COSMIC: COSV60075644; COSMIC: COSV60075644;