rs1059393

Variant names:

• chr18-672836-A-G
• rs1059393
• NM_017512.7:c.*1469T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017512.7(ENOSF1):​c.*1469T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,544,122 control chromosomes in the GnomAD database, including 16,105 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 0.13 (1295 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14810 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35

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=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOSF1	NM_017512.7	c.*1469T>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000647584.2	NP_059982.2
TYMS	NM_001071.4	c.805-24A>G		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	c.*1469T>C		3_prime_UTR_variant	Exon 16 of 16		NM_017512.7	ENSP00000497230.2
TYMS	ENST00000323274.15	c.805-24A>G		intron_variant	Intron 6 of 6	1	NM_001071.4	ENSP00000315644.10

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19121 AN: 152118 Hom.: 1291 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.0853

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.117 AC: 28773 AN: 246432 AF XY: 0.119

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.0633

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.00418

Gnomad FIN exome AF: 0.151

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.141 AC: 196084 AN: 1391886 Hom.: 14810 Cov.: 31 AF XY: 0.139 AC XY: 95171 AN XY: 684788

Gnomad4 AFR exome AF: 0.123 AC: 3987 AN: 32302

Gnomad4 AMR exome AF: 0.0676 AC: 2874 AN: 42536

Gnomad4 ASJ exome AF: 0.104 AC: 2539 AN: 24406

Gnomad4 EAS exome AF: 0.00297 AC: 115 AN: 38664

Gnomad4 SAS exome AF: 0.0947 AC: 7405 AN: 78176

Gnomad4 FIN exome AF: 0.154 AC: 7921 AN: 51476

Gnomad4 NFE exome AF: 0.154 AC: 163285 AN: 1062030

Gnomad4 Remaining exome AF: 0.131 AC: 7427 AN: 56832

GnomAD4 genome AF: 0.126 AC: 19138 AN: 152236 Hom.: 1295 Cov.: 33 AF XY: 0.122 AC XY: 9118 AN XY: 74444

Gnomad4 AFR AF: 0.120 AC: 0.120184 AN: 0.120184

Gnomad4 AMR AF: 0.0850 AC: 0.0849895 AN: 0.0849895

Gnomad4 ASJ AF: 0.102 AC: 0.101729 AN: 0.101729

Gnomad4 EAS AF: 0.00289 AC: 0.00289464 AN: 0.00289464

Gnomad4 SAS AF: 0.0860 AC: 0.0860282 AN: 0.0860282

Gnomad4 FIN AF: 0.146 AC: 0.145633 AN: 0.145633

Gnomad4 NFE AF: 0.148 AC: 0.14819 AN: 0.14819

Gnomad4 OTH AF: 0.120 AC: 0.120151 AN: 0.120151

Alfa AF: 0.139 Hom.: 2159

Bravo AF: 0.121

Asia WGS AF: 0.0430 AC: 151 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.4
DANN	Benign	0.58
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1059393; hg19: chr18-672836; COSMIC: COSV51890614; COSMIC: COSV51890614;