rs2847149

chr18-666371-G-A

Variant summary

Our verdict is Benign. Variant got -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

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:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
TYMS	NM_001071.4	c.455-2701G>A		intron_variant		ENST00000323274.15
ENOSF1	XM_047437611.1	c.-1095C>T		5_prime_UTR_variant	2/2
TYMS	NM_001354867.2	c.454+4051G>A		intron_variant
TYMS	NM_001354868.2	c.206-2701G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TYMS	ENST00000323274.15	c.455-2701G>A		intron_variant		1	NM_001071.4	P1
TYMS	ENST00000323224.7	c.454+4051G>A		intron_variant		1
TYMS	ENST00000323250.9	c.206-2701G>A		intron_variant		1
TYMS	ENST00000579128.1	n.533-2701G>A		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR AF: 0.775

Gnomad4 AMR AF: 0.427

Gnomad4 ASJ AF: 0.485

Gnomad4 EAS AF: 0.683

Gnomad4 SAS AF: 0.531

Gnomad4 FIN AF: 0.447

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.547

Alfa AF: 0.481 Hom.: 17814

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
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: rs2847149; hg19: chr18-666371; COSMIC: COSV60076327; COSMIC: COSV60076327;