18-673016-C-T

Variant names:

• chr18-673016-C-T
• rs699517
• NM_017512.7:c.*1289G>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.*1289G>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 0.341 in 1,532,406 control chromosomes in the GnomAD database, including 95,046 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 (13096 hom., cov: 32)
  • Exomes 𝑓: 0.33 (81950 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.241
• Publications: 78 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017512.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOSF1	NM_017512.7	MANE Select	c.*1289G>A		3_prime_UTR	Exon 16 of 16	NP_059982.2
	TYMS	NM_001071.4	MANE Select	c.*19C>T		3_prime_UTR	Exon 7 of 7	NP_001062.1	Q53Y97
	ENOSF1	NM_001354067.2		c.*1289G>A		3_prime_UTR	Exon 16 of 16	NP_001340996.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOSF1	ENST00000647584.2	MANE Select	c.*1289G>A		3_prime_UTR	Exon 16 of 16	ENSP00000497230.2	Q7L5Y1-1
	TYMS	ENST00000323274.15	TSL:1 MANE Select	c.*19C>T		3_prime_UTR	Exon 7 of 7	ENSP00000315644.10	P04818-1
	ENOSF1	ENST00000383578.7	TSL:1	c.*205G>A		3_prime_UTR	Exon 16 of 16	ENSP00000373072.3	Q7L5Y1-2

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60373 AN: 151880 Hom.: 13081 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.399

GnomAD2 exomes AF: 0.379 AC: 94169 AN: 248232 AF XY: 0.380

Gnomad AFR exome AF: 0.554

Gnomad AMR exome AF: 0.325

Gnomad ASJ exome AF: 0.382

Gnomad EAS exome AF: 0.692

Gnomad FIN exome AF: 0.310

Gnomad NFE exome AF: 0.316

Gnomad OTH exome AF: 0.356

GnomAD4 exome AF: 0.334 AC: 461516 AN: 1380408 Hom.: 81950 Cov.: 33 AF XY: 0.338 AC XY: 229104 AN XY: 678178

African (AFR) AF: 0.563 AC: 18283 AN: 32490

American (AMR) AF: 0.323 AC: 14003 AN: 43358

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 9252 AN: 24304

East Asian (EAS) AF: 0.668 AC: 25777 AN: 38586

South Asian (SAS) AF: 0.441 AC: 33163 AN: 75182

European-Finnish (FIN) AF: 0.301 AC: 15286 AN: 50754

Middle Eastern (MID) AF: 0.489 AC: 2665 AN: 5452

European-Non Finnish (NFE) AF: 0.306 AC: 322410 AN: 1054040

Other (OTH) AF: 0.368 AC: 20677 AN: 56242

GnomAD4 genome AF: 0.398 AC: 60420 AN: 151998 Hom.: 13096 Cov.: 32 AF XY: 0.401 AC XY: 29828 AN XY: 74292

African (AFR) AF: 0.552 AC: 22862 AN: 41444

American (AMR) AF: 0.335 AC: 5113 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1365 AN: 3470

East Asian (EAS) AF: 0.685 AC: 3549 AN: 5180

South Asian (SAS) AF: 0.447 AC: 2149 AN: 4810

European-Finnish (FIN) AF: 0.304 AC: 3214 AN: 10560

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

European-Non Finnish (NFE) AF: 0.309 AC: 21031 AN: 67956

Other (OTH) AF: 0.401 AC: 846 AN: 2108

Alfa AF: 0.360 Hom.: 14669

Bravo AF: 0.407

Asia WGS AF: 0.575 AC: 2003 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.59
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs699517; hg19: chr18-673016; COSMIC: COSV51890234; COSMIC: COSV51890234;