rs2847153

Variant names:

• chr18-661647-G-A
• rs2847153
• NM_001071.4:c.280-499G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001071.4(TYMS):​c.280-499G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,176 control chromosomes in the GnomAD database, including 3,993 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 0.22 (3993 hom., cov: 33)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.47
• Publications: 52 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4	c.280-499G>A		intron_variant	Intron 2 of 6	ENST00000323274.15	NP_001062.1
TYMS	NM_001354867.2	c.280-499G>A		intron_variant	Intron 2 of 5		NP_001341796.1
TYMS	NM_001354868.2	c.205+3700G>A		intron_variant	Intron 1 of 4		NP_001341797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TYMS	ENST00000323274.15	c.280-499G>A		intron_variant	Intron 2 of 6	1	NM_001071.4	ENSP00000315644.10
TYMS	ENST00000323224.7	c.280-499G>A		intron_variant	Intron 2 of 5	1		ENSP00000314727.7
TYMS	ENST00000323250.9	c.205+3700G>A		intron_variant	Intron 1 of 4	1		ENSP00000314902.5
TYMS	ENST00000579128.1	n.358-499G>A		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes AF: 0.224 AC: 34081 AN: 152056 Hom.: 3991 Cov.: 33

Gnomad AFR AF: 0.248

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.362

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.233

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

GnomAD4 genome AF: 0.224 AC: 34102 AN: 152176 Hom.: 3993 Cov.: 33 AF XY: 0.227 AC XY: 16905 AN XY: 74404

African (AFR) AF: 0.248 AC: 10277 AN: 41514

American (AMR) AF: 0.215 AC: 3282 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3472

East Asian (EAS) AF: 0.361 AC: 1866 AN: 5166

South Asian (SAS) AF: 0.354 AC: 1708 AN: 4822

European-Finnish (FIN) AF: 0.164 AC: 1735 AN: 10596

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13719 AN: 67992

Other (OTH) AF: 0.238 AC: 503 AN: 2112

Alfa AF: 0.218 Hom.: 9414

Bravo AF: 0.228

Asia WGS AF: 0.383 AC: 1333 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.16
DANN	Benign	0.43
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2847153; hg19: chr18-661647;