rs2847149

Variant names:

• chr18-666371-G-A
• rs2847149
• NM_001071.4:c.455-2701G>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.455-2701G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 151,648 control chromosomes in the GnomAD database, including 24,567 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 (24567 hom., cov: 30)
• Consequence: TYMS NM_001071.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.902
• Publications: 16 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]

ENOSF1 (HGNC:30365): (enolase superfamily member 1) This gene can encode a mitochondrial enzyme that is thought to convert L-fuconate to 2-keto-3-deoxy-L-fuconate. This locus was originally identified as the source of antisense RNAs of the adjacent thymidylate synthase gene. Splice variants at this locus may contain an alternate 3' exon that is complementary to the 3'UTR and terminal intron of the thymidylate synthase (TS) RNA and may downregulate TS expression. [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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TYMS	NM_001071.4	c.455-2701G>A		intron_variant	Intron 3 of 6	ENST00000323274.15	NP_001062.1
ENOSF1	XM_047437611.1	c.-1095C>T		5_prime_UTR_variant	Exon 2 of 2		XP_047293567.1
TYMS	NM_001354867.2	c.454+4051G>A		intron_variant	Intron 3 of 5		NP_001341796.1
TYMS	NM_001354868.2	c.206-2701G>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.455-2701G>A		intron_variant	Intron 3 of 6	1	NM_001071.4	ENSP00000315644.10
TYMS	ENST00000323224.7	c.454+4051G>A		intron_variant	Intron 3 of 5	1		ENSP00000314727.7
TYMS	ENST00000323250.9	c.206-2701G>A		intron_variant	Intron 1 of 4	1		ENSP00000314902.5
TYMS	ENST00000579128.1	n.533-2701G>A		intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.550 AC: 83417 AN: 151530 Hom.: 24521 Cov.: 30

Gnomad AFR AF: 0.775

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.485

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.533

Gnomad FIN AF: 0.447

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.542

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

GnomAD4 genome AF: 0.551 AC: 83505 AN: 151648 Hom.: 24567 Cov.: 30 AF XY: 0.549 AC XY: 40706 AN XY: 74086

African (AFR) AF: 0.775 AC: 32018 AN: 41322

American (AMR) AF: 0.427 AC: 6509 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 1682 AN: 3470

East Asian (EAS) AF: 0.683 AC: 3500 AN: 5124

South Asian (SAS) AF: 0.531 AC: 2549 AN: 4798

European-Finnish (FIN) AF: 0.447 AC: 4710 AN: 10534

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.456 AC: 30905 AN: 67840

Other (OTH) AF: 0.547 AC: 1153 AN: 2106

Alfa AF: 0.490 Hom.: 24372

Bravo AF: 0.560

Asia WGS AF: 0.629 AC: 2189 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.45
DANN	Benign	0.53
PhyloP100		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2847149; hg19: chr18-666371; COSMIC: COSV60076327; COSMIC: COSV60076327;