18-670414-C-T

Variant names:

• chr18-670414-C-T
• rs2853532
• NM_017512.7:c.*3891G>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.*3891G>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 0.365 in 344,252 control chromosomes in the GnomAD database, including 25,585 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 (12963 hom., cov: 31)
  • Exomes 𝑓: 0.34 (12622 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.515
• Publications: 15 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 = 0.66 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOSF1	NM_017512.7	c.*3891G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000647584.2	NP_059982.2
TYMS	NM_001071.4	c.557-278C>T		intron_variant	Intron 4 of 6	ENST00000323274.15	NP_001062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENOSF1	ENST00000647584.2	c.*3891G>A		3_prime_UTR_variant	Exon 16 of 16		NM_017512.7	ENSP00000497230.2
TYMS	ENST00000323274.15	c.557-278C>T		intron_variant	Intron 4 of 6	1	NM_001071.4	ENSP00000315644.10

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60056 AN: 151796 Hom.: 12947 Cov.: 31

Gnomad AFR AF: 0.550

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.679

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.398

GnomAD4 exome AF: 0.342 AC: 65700 AN: 192334 Hom.: 12622 Cov.: 0 AF XY: 0.343 AC XY: 33923 AN XY: 98872

African (AFR) AF: 0.557 AC: 3340 AN: 6000

American (AMR) AF: 0.312 AC: 2333 AN: 7480

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 2495 AN: 6634

East Asian (EAS) AF: 0.647 AC: 8879 AN: 13716

South Asian (SAS) AF: 0.399 AC: 4476 AN: 11208

European-Finnish (FIN) AF: 0.288 AC: 3680 AN: 12770

Middle Eastern (MID) AF: 0.443 AC: 417 AN: 942

European-Non Finnish (NFE) AF: 0.294 AC: 35736 AN: 121434

Other (OTH) AF: 0.358 AC: 4344 AN: 12150

GnomAD4 genome AF: 0.396 AC: 60105 AN: 151918 Hom.: 12963 Cov.: 31 AF XY: 0.400 AC XY: 29653 AN XY: 74218

African (AFR) AF: 0.550 AC: 22776 AN: 41404

American (AMR) AF: 0.333 AC: 5082 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1363 AN: 3470

East Asian (EAS) AF: 0.679 AC: 3503 AN: 5162

South Asian (SAS) AF: 0.445 AC: 2135 AN: 4802

European-Finnish (FIN) AF: 0.303 AC: 3196 AN: 10542

Middle Eastern (MID) AF: 0.473 AC: 139 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20912 AN: 67954

Other (OTH) AF: 0.400 AC: 847 AN: 2116

Alfa AF: 0.346 Hom.: 13756

Bravo AF: 0.405

Asia WGS AF: 0.572 AC: 1991 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	0.51
DANN	Benign	0.45
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2853532; hg19: chr18-670414;