rs1059394

Variant names:

• chr18-672792-C-T
• rs1059394
• NM_017512.7:c.*1513G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 23 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ENOSF1	NM_017512.7	c.*1513G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000647584.2	NP_059982.2
TYMS	NM_001071.4	c.805-68C>T		intron_variant	Intron 6 of 6	ENST00000323274.15	NP_001062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENOSF1	ENST00000647584.2	c.*1513G>A		3_prime_UTR_variant	Exon 16 of 16		NM_017512.7	ENSP00000497230.2
TYMS	ENST00000323274.15	c.805-68C>T		intron_variant	Intron 6 of 6	1	NM_001071.4	ENSP00000315644.10

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

African (AFR) AF: 0.563 AC: 17203 AN: 30544

American (AMR) AF: 0.319 AC: 11662 AN: 36538

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 8103 AN: 21242

East Asian (EAS) AF: 0.669 AC: 25621 AN: 38314

South Asian (SAS) AF: 0.438 AC: 28779 AN: 65652

European-Finnish (FIN) AF: 0.300 AC: 14708 AN: 49044

Middle Eastern (MID) AF: 0.488 AC: 2515 AN: 5150

European-Non Finnish (NFE) AF: 0.306 AC: 313368 AN: 1022802

Other (OTH) AF: 0.367 AC: 19816 AN: 53962

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

African (AFR) AF: 0.552 AC: 22872 AN: 41432

American (AMR) AF: 0.335 AC: 5123 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1365 AN: 3472

East Asian (EAS) AF: 0.684 AC: 3539 AN: 5172

South Asian (SAS) AF: 0.446 AC: 2144 AN: 4804

European-Finnish (FIN) AF: 0.305 AC: 3221 AN: 10558

Middle Eastern (MID) AF: 0.473 AC: 138 AN: 292

European-Non Finnish (NFE) AF: 0.309 AC: 21035 AN: 67984

Other (OTH) AF: 0.402 AC: 848 AN: 2110

Alfa AF: 0.355 Hom.: 12656

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
PhyloP100		0.072
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: rs1059394; hg19: chr18-672792; COSMIC: COSV51894657; COSMIC: COSV51894657;