chr18-671520-C-T

Variant names:

• chr18-671520-C-T
• rs2853536
• NM_017512.7:c.*2785G>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.*2785G>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 0.354 in 988,694 control chromosomes in the GnomAD database, including 67,077 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 (13104 hom., cov: 32)
  • Exomes 𝑓: 0.35 (53973 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 16 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 = 0.667 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOSF1	NM_017512.7	c.*2785G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000647584.2	NP_059982.2
TYMS	NM_001071.4	c.804+69C>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.*2785G>A		3_prime_UTR_variant	Exon 16 of 16		NM_017512.7	ENSP00000497230.2
TYMS	ENST00000323274.15	c.804+69C>T		intron_variant	Intron 6 of 6	1	NM_001071.4	ENSP00000315644.10

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60396 AN: 151888 Hom.: 13089 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.166

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.399

GnomAD4 exome AF: 0.346 AC: 289212 AN: 836688 Hom.: 53973 Cov.: 11 AF XY: 0.350 AC XY: 154451 AN XY: 441520

African (AFR) AF: 0.556 AC: 11708 AN: 21058

American (AMR) AF: 0.324 AC: 13531 AN: 41782

Ashkenazi Jewish (ASJ) AF: 0.381 AC: 8401 AN: 22070

East Asian (EAS) AF: 0.666 AC: 24518 AN: 36808

South Asian (SAS) AF: 0.439 AC: 31722 AN: 72212

European-Finnish (FIN) AF: 0.301 AC: 15750 AN: 52248

Middle Eastern (MID) AF: 0.482 AC: 2193 AN: 4554

European-Non Finnish (NFE) AF: 0.305 AC: 166673 AN: 546128

Other (OTH) AF: 0.369 AC: 14716 AN: 39828

GnomAD4 genome AF: 0.398 AC: 60443 AN: 152006 Hom.: 13104 Cov.: 32 AF XY: 0.402 AC XY: 29852 AN XY: 74330

African (AFR) AF: 0.552 AC: 22871 AN: 41442

American (AMR) AF: 0.335 AC: 5123 AN: 15270

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

East Asian (EAS) AF: 0.685 AC: 3548 AN: 5176

South Asian (SAS) AF: 0.446 AC: 2146 AN: 4814

European-Finnish (FIN) AF: 0.304 AC: 3209 AN: 10550

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

European-Non Finnish (NFE) AF: 0.310 AC: 21044 AN: 67966

Other (OTH) AF: 0.401 AC: 847 AN: 2110

Alfa AF: 0.228 Hom.: 543

Bravo AF: 0.407

Asia WGS AF: 0.576 AC: 2005 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.75
DANN	Benign	0.53
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs2853536; hg19: chr18-671520; COSMIC: COSV51893080; COSMIC: COSV51893080;