rs1004474

Positions:

• chr18-660383-A-G

Variant summary

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

The NM_001071.4(TYMS):​c.279+669A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 152,062 control chromosomes in the GnomAD database, including 20,193 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 0.51 (20193 hom., cov: 32)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TYMS	NM_001071.4	c.279+669A>G		intron_variant		ENST00000323274.15
TYMS	NM_001354867.2	c.279+669A>G		intron_variant
TYMS	NM_001354868.2	c.205+2436A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMS	ENST00000323274.15	c.279+669A>G		intron_variant		1	NM_001071.4	P1
TYMS	ENST00000323224.7	c.279+669A>G		intron_variant		1
TYMS	ENST00000323250.9	c.205+2436A>G		intron_variant		1
TYMS	ENST00000579128.1	n.357+669A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.505 AC: 76750 AN: 151944 Hom.: 20170 Cov.: 32

Gnomad AFR AF: 0.669

Gnomad AMI AF: 0.330

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.445

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.454

Gnomad OTH AF: 0.508

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

GnomAD4 genome AF: 0.505 AC: 76810 AN: 152062 Hom.: 20193 Cov.: 32 AF XY: 0.502 AC XY: 37302 AN XY: 74330

Gnomad4 AFR AF: 0.669

Gnomad4 AMR AF: 0.406

Gnomad4 ASJ AF: 0.479

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.514

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.509

Alfa AF: 0.472 Hom.: 22685

Bravo AF: 0.512

Asia WGS AF: 0.521 AC: 1815 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.020
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1004474; hg19: chr18-660383;