rs1001761

Positions:

• chr18-662103-G-A
• chr18-662103-G-T

Variant summary

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

The NM_001071.4(TYMS):​c.280-43G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.483 in 1,553,636 control chromosomes in the GnomAD database, including 186,891 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 0.55 (24727 hom., cov: 31)
  • Exomes 𝑓: 0.48 (162164 hom.)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115

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]

TYMS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYMS	NM_001071.4	c.280-43G>A		intron_variant		ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2	c.280-43G>A		intron_variant			NP_001341796.1
TYMS	NM_001354868.2	c.205+4156G>A		intron_variant			NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.280-43G>A		intron_variant		1	NM_001071.4	ENSP00000315644.10
TYMS	ENST00000323224.7	c.280-43G>A		intron_variant		1		ENSP00000314727.7
TYMS	ENST00000323250.9	c.205+4156G>A		intron_variant		1		ENSP00000314902.5
TYMS	ENST00000579128.1	n.358-43G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83794 AN: 151882 Hom.: 24681 Cov.: 31

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.683

Gnomad SAS AF: 0.549

Gnomad FIN AF: 0.450

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.543

GnomAD3 exomes AF: 0.503 AC: 101620 AN: 202044 Hom.: 26903 AF XY: 0.502 AC XY: 54017 AN XY: 107574

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.378

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.689

Gnomad SAS exome AF: 0.548

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.463

Gnomad OTH exome AF: 0.480

GnomAD4 exome AF: 0.476 AC: 666635 AN: 1401636 Hom.: 162164 Cov.: 30 AF XY: 0.477 AC XY: 330661 AN XY: 693288

Gnomad4 AFR exome AF: 0.788

Gnomad4 AMR exome AF: 0.384

Gnomad4 ASJ exome AF: 0.473

Gnomad4 EAS exome AF: 0.665

Gnomad4 SAS exome AF: 0.542

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.457

Gnomad4 OTH exome AF: 0.503

GnomAD4 genome AF: 0.552 AC: 83882 AN: 152000 Hom.: 24727 Cov.: 31 AF XY: 0.551 AC XY: 40969 AN XY: 74330

Gnomad4 AFR AF: 0.776

Gnomad4 AMR AF: 0.427

Gnomad4 ASJ AF: 0.485

Gnomad4 EAS AF: 0.682

Gnomad4 SAS AF: 0.547

Gnomad4 FIN AF: 0.450

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.548

Alfa AF: 0.481 Hom.: 19062

Bravo AF: 0.560

Asia WGS AF: 0.633 AC: 2205 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1001761; hg19: chr18-662103; COSMIC: COSV60074405; COSMIC: COSV60074405;