18-675787-C-T

Variant names:

• chr18-675787-C-T
• rs2260821
• NM_017512.7:c.1149-385G>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.1149-385G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 152,106 control chromosomes in the GnomAD database, including 44,530 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 0.76 (44530 hom., cov: 32)
• Consequence: ENOSF1 NM_017512.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.09
• Publications: 5 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.851 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.1149-385G>A		intron	N/A	NP_059982.2
	ENOSF1	NM_001354067.2		c.1293-385G>A		intron	N/A	NP_001340996.1
	ENOSF1	NM_202758.5		c.1251-385G>A		intron	N/A	NP_974487.2	A0A3F2YNX7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOSF1	ENST00000647584.2	MANE Select	c.1149-385G>A		intron	N/A	ENSP00000497230.2	Q7L5Y1-1
	ENOSF1	ENST00000383578.7	TSL:1	c.903-385G>A		intron	N/A	ENSP00000373072.3	Q7L5Y1-2
	ENOSF1	ENST00000581475.5	TSL:1	n.*536-385G>A		intron	N/A	ENSP00000464614.1	J3QSB6

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115859 AN: 151988 Hom.: 44487 Cov.: 32

Gnomad AFR AF: 0.858

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.734

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.758

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.762 AC: 115956 AN: 152106 Hom.: 44530 Cov.: 32 AF XY: 0.758 AC XY: 56320 AN XY: 74336

African (AFR) AF: 0.858 AC: 35632 AN: 41520

American (AMR) AF: 0.740 AC: 11300 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.734 AC: 2543 AN: 3466

East Asian (EAS) AF: 0.691 AC: 3563 AN: 5158

South Asian (SAS) AF: 0.606 AC: 2920 AN: 4822

European-Finnish (FIN) AF: 0.698 AC: 7370 AN: 10558

Middle Eastern (MID) AF: 0.789 AC: 232 AN: 294

European-Non Finnish (NFE) AF: 0.738 AC: 50148 AN: 67984

Other (OTH) AF: 0.762 AC: 1611 AN: 2114

Alfa AF: 0.754 Hom.: 54849

Bravo AF: 0.772

Asia WGS AF: 0.685 AC: 2386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	9.4
DANN	Benign	0.35
PhyloP100		-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: rs2260821; hg19: chr18-675787;