18-674012-T-G

Variant names:

• chr18-674012-T-G
• rs8423
• NM_017512.7:c.*293A>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.*293A>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 0.389 in 231,078 control chromosomes in the GnomAD database, including 19,064 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 (13114 hom., cov: 32)
  • Exomes 𝑓: 0.37 (5950 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452
• Publications: 11 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.667 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.*293A>C		3_prime_UTR	Exon 16 of 16	NP_059982.2
	ENOSF1	NM_001354067.2		c.*293A>C		3_prime_UTR	Exon 16 of 16	NP_001340996.1
	ENOSF1	NM_202758.5		c.*293A>C		3_prime_UTR	Exon 15 of 15	NP_974487.2	A0A3F2YNX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOSF1	ENST00000647584.2	MANE Select	c.*293A>C		3_prime_UTR	Exon 16 of 16	ENSP00000497230.2	Q7L5Y1-1
	ENOSF1	ENST00000383578.7	TSL:1	c.*144+149A>C		intron	N/A	ENSP00000373072.3	Q7L5Y1-2
	ENOSF1	ENST00000581475.5	TSL:1	n.*1012A>C		non_coding_transcript_exon	Exon 14 of 14	ENSP00000464614.1	J3QSB6

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60365 AN: 151788 Hom.: 13099 Cov.: 32

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.686

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

GnomAD4 exome AF: 0.372 AC: 29484 AN: 79172 Hom.: 5950 Cov.: 0 AF XY: 0.377 AC XY: 15213 AN XY: 40390

African (AFR) AF: 0.571 AC: 1455 AN: 2548

American (AMR) AF: 0.332 AC: 912 AN: 2750

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1198 AN: 2964

East Asian (EAS) AF: 0.696 AC: 3451 AN: 4956

South Asian (SAS) AF: 0.476 AC: 1999 AN: 4202

European-Finnish (FIN) AF: 0.323 AC: 1260 AN: 3906

Middle Eastern (MID) AF: 0.488 AC: 204 AN: 418

European-Non Finnish (NFE) AF: 0.326 AC: 16930 AN: 51988

Other (OTH) AF: 0.381 AC: 2075 AN: 5440

GnomAD4 genome AF: 0.398 AC: 60412 AN: 151906 Hom.: 13114 Cov.: 32 AF XY: 0.402 AC XY: 29822 AN XY: 74252

African (AFR) AF: 0.552 AC: 22852 AN: 41386

American (AMR) AF: 0.335 AC: 5120 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1381 AN: 3468

East Asian (EAS) AF: 0.685 AC: 3541 AN: 5166

South Asian (SAS) AF: 0.446 AC: 2148 AN: 4814

European-Finnish (FIN) AF: 0.304 AC: 3203 AN: 10552

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

European-Non Finnish (NFE) AF: 0.310 AC: 21031 AN: 67948

Other (OTH) AF: 0.401 AC: 845 AN: 2106

Alfa AF: 0.341 Hom.: 5635

Bravo AF: 0.407

Asia WGS AF: 0.576 AC: 2003 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.84
PhyloP100		0.45
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: rs8423; hg19: chr18-674012;