rs1059394

chr18-672792-C-T

Variant summary

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

The NM_017512.7(ENOSF1):c.*1513G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,475,262 control chromosomes in the GnomAD database, including 91,444 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 0.40 (13109 hom., cov: 32)
  • Exomes 𝑓: 0.33 (78335 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0720

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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENOSF1	NM_017512.7	c.*1513G>A		3_prime_UTR_variant	16/16	ENST00000647584.2
TYMS	NM_001071.4	c.805-68C>T		intron_variant		ENST00000323274.15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENOSF1	ENST00000647584.2	c.*1513G>A		3_prime_UTR_variant	16/16		NM_017512.7	P1
TYMS	ENST00000323274.15	c.805-68C>T		intron_variant		1	NM_001071.4	P1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60390 AN: 151896 Hom.: 13094 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.399

GnomAD4 exome AF: 0.334 AC: 441775 AN: 1323248 Hom.: 78335 Cov.: 21 AF XY: 0.337 AC XY: 218461 AN XY: 648498

Gnomad4 AFR exome AF: 0.563

Gnomad4 AMR exome AF: 0.319

Gnomad4 ASJ exome AF: 0.381

Gnomad4 EAS exome AF: 0.669

Gnomad4 SAS exome AF: 0.438

Gnomad4 FIN exome AF: 0.300

Gnomad4 NFE exome AF: 0.306

Gnomad4 OTH exome AF: 0.367

GnomAD4 genome AF: 0.398 AC: 60437 AN: 152014 Hom.: 13109 Cov.: 32 AF XY: 0.402 AC XY: 29840 AN XY: 74306

Gnomad4 AFR AF: 0.552

Gnomad4 AMR AF: 0.335

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.684

Gnomad4 SAS AF: 0.446

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.309

Gnomad4 OTH AF: 0.402

Alfa AF: 0.338 Hom.: 7674

Bravo AF: 0.407

Asia WGS AF: 0.575 AC: 2003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	4.1
Dann	Benign	0.77

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: rs1059394; hg19: chr18-672792; COSMIC: COSV51894657; COSMIC: COSV51894657;