rs3826626

Positions:

• chr18-670888-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017512.7(ENOSF1):​c.*3417A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,612,726 control chromosomes in the GnomAD database, including 2,427 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 0.067 (830 hom., cov: 32)
  • Exomes 𝑓: 0.016 (1597 hom.)
• Consequence: ENOSF1 NM_017512.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.700

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENOSF1	NM_017512.7	c.*3417A>G		3_prime_UTR_variant	16/16	ENST00000647584.2
TYMS	NM_001071.4	c.732+21T>C		intron_variant		ENST00000323274.15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENOSF1	ENST00000647584.2	c.*3417A>G		3_prime_UTR_variant	16/16		NM_017512.7	P1
TYMS	ENST00000323274.15	c.732+21T>C		intron_variant		1	NM_001071.4	P1

Frequencies

GnomAD3 genomes AF: 0.0669 AC: 10169 AN: 151998 Hom.: 827 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0289

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0678

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0521

GnomAD3 exomes AF: 0.0447 AC: 11143 AN: 249496 Hom.: 922 AF XY: 0.0384 AC XY: 5171 AN XY: 134772

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.0375

Gnomad ASJ exome AF: 0.00733

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.0150

Gnomad FIN exome AF: 0.0679

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0158 AC: 23053 AN: 1460610 Hom.: 1597 Cov.: 31 AF XY: 0.0147 AC XY: 10708 AN XY: 726534

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.0359

Gnomad4 ASJ exome AF: 0.00694

Gnomad4 EAS exome AF: 0.198

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.0645

Gnomad4 NFE exome AF: 0.000819

Gnomad4 OTH exome AF: 0.0291

GnomAD4 genome AF: 0.0670 AC: 10194 AN: 152116 Hom.: 830 Cov.: 32 AF XY: 0.0697 AC XY: 5182 AN XY: 74348

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.0289

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.230

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.0678

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.0516

Alfa AF: 0.0182 Hom.: 208

Bravo AF: 0.0719

Asia WGS AF: 0.104 AC: 360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.10
DANN	Benign	0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3826626; hg19: chr18-670888; COSMIC: COSV51890513; COSMIC: COSV51890513;