chr18-660383-A-G

Variant names:

• chr18-660383-A-G
• rs1004474
• NM_001071.4:c.279+669A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 19 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]

ACMG classification

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMS	NM_001071.4	MANE Select	c.279+669A>G		intron	N/A	NP_001062.1
	TYMS	NM_001354867.2		c.279+669A>G		intron	N/A	NP_001341796.1
	TYMS	NM_001354868.2		c.205+2436A>G		intron	N/A	NP_001341797.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TYMS	ENST00000323274.15	TSL:1 MANE Select	c.279+669A>G		intron	N/A	ENSP00000315644.10
	TYMS	ENST00000323224.7	TSL:1	c.279+669A>G		intron	N/A	ENSP00000314727.7
	TYMS	ENST00000323250.9	TSL:1	c.205+2436A>G		intron	N/A	ENSP00000314902.5

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

African (AFR) AF: 0.669 AC: 27772 AN: 41484

American (AMR) AF: 0.406 AC: 6193 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1658 AN: 3462

East Asian (EAS) AF: 0.444 AC: 2296 AN: 5166

South Asian (SAS) AF: 0.514 AC: 2474 AN: 4812

European-Finnish (FIN) AF: 0.382 AC: 4039 AN: 10580

Middle Eastern (MID) AF: 0.599 AC: 176 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30826 AN: 67976

Other (OTH) AF: 0.509 AC: 1075 AN: 2112

Alfa AF: 0.478 Hom.: 65198

Bravo AF: 0.512

Asia WGS AF: 0.521 AC: 1815 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.020
DANN	Benign	0.46
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1004474; hg19: chr18-660383;