rs2612100

chr18-672363-G-A

Variant summary

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

The NM_017512.7(ENOSF1):c.*1942C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 152,122 control chromosomes in the GnomAD database, including 15,317 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 0.42 (15305 hom., cov: 32)
  • Exomes 𝑓: 0.35 (12 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08

Genes affected

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]

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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENOSF1	NM_017512.7	c.*1942C>T		3_prime_UTR_variant	16/16	ENST00000647584.2
TYMS	NM_001071.4	c.805-497G>A		intron_variant		ENST00000323274.15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENOSF1	ENST00000647584.2	c.*1942C>T		3_prime_UTR_variant	16/16		NM_017512.7	P1
TYMS	ENST00000323274.15	c.805-497G>A		intron_variant		1	NM_001071.4	P1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64128 AN: 151832 Hom.: 15279 Cov.: 32

Gnomad AFR AF: 0.638

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.418

GnomAD4 exome AF: 0.349 AC: 60 AN: 172 Hom.: 12 Cov.: 0 AF XY: 0.411 AC XY: 37 AN XY: 90

Gnomad4 AMR exome AF: 0.267

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.323

Gnomad4 OTH exome AF: 0.625

GnomAD4 genome AF: 0.422 AC: 64189 AN: 151950 Hom.: 15305 Cov.: 32 AF XY: 0.425 AC XY: 31565 AN XY: 74256

Gnomad4 AFR AF: 0.639

Gnomad4 AMR AF: 0.345

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.685

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.420

Alfa AF: 0.362 Hom.: 1855

Bravo AF: 0.435

Asia WGS AF: 0.579 AC: 2016 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.033
Dann	Benign	0.36

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: rs2612100; hg19: chr18-672363;