18-671648-A-T

Variant names:

• chr18-671648-A-T
• rs2853537
• NM_017512.7:c.*2657T>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.*2657T>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 0.375 in 602,476 control chromosomes in the GnomAD database, including 45,874 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 (13418 hom., cov: 33)
  • Exomes 𝑓: 0.37 (32456 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.380
• Publications: 8 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOSF1	NM_017512.7	c.*2657T>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000647584.2	NP_059982.2
TYMS	NM_001071.4	c.804+197A>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.*2657T>A		3_prime_UTR_variant	Exon 16 of 16		NM_017512.7	ENSP00000497230.2
TYMS	ENST00000323274.15	c.804+197A>T		intron_variant	Intron 6 of 6	1	NM_001071.4	ENSP00000315644.10

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61401 AN: 151898 Hom.: 13403 Cov.: 33

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.165

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.685

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.324

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.366 AC: 164724 AN: 450460 Hom.: 32456 Cov.: 3 AF XY: 0.368 AC XY: 89169 AN XY: 241996

African (AFR) AF: 0.557 AC: 6433 AN: 11546

American (AMR) AF: 0.317 AC: 4872 AN: 15350

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 5377 AN: 14030

East Asian (EAS) AF: 0.660 AC: 19166 AN: 29060

South Asian (SAS) AF: 0.441 AC: 19754 AN: 44774

European-Finnish (FIN) AF: 0.319 AC: 9779 AN: 30642

Middle Eastern (MID) AF: 0.474 AC: 1488 AN: 3138

European-Non Finnish (NFE) AF: 0.319 AC: 87908 AN: 275852

Other (OTH) AF: 0.382 AC: 9947 AN: 26068

GnomAD4 genome AF: 0.404 AC: 61447 AN: 152016 Hom.: 13418 Cov.: 33 AF XY: 0.409 AC XY: 30368 AN XY: 74310

African (AFR) AF: 0.553 AC: 22937 AN: 41446

American (AMR) AF: 0.337 AC: 5155 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1372 AN: 3468

East Asian (EAS) AF: 0.685 AC: 3539 AN: 5168

South Asian (SAS) AF: 0.449 AC: 2159 AN: 4808

European-Finnish (FIN) AF: 0.324 AC: 3419 AN: 10554

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21720 AN: 67976

Other (OTH) AF: 0.405 AC: 856 AN: 2114

Alfa AF: 0.356 Hom.: 1261

Bravo AF: 0.412

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.90
DANN	Benign	0.39
PhyloP100		-0.38
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: rs2853537; hg19: chr18-671648; COSMIC: COSV51895977; COSMIC: COSV51895977;