rs2612086

Variant names:

• chr18-691266-A-G
• rs2612086
• NM_017512.7:c.434T>C

Variant summary

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

The NM_017512.7(ENOSF1):​c.434T>C​(p.Met145Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,612,634 control chromosomes in the GnomAD database, including 101,708 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (8967 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92741 hom.)
• Consequence: ENOSF1 NM_017512.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0220

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051549077).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENOSF1	NM_017512.7	c.434T>C	p.Met145Thr	missense_variant	Exon 6 of 16	ENST00000647584.2	NP_059982.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENOSF1	ENST00000647584.2	c.434T>C	p.Met145Thr	missense_variant	Exon 6 of 16		NM_017512.7	ENSP00000497230.2

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51351 AN: 151994 Hom.: 8960 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.0950

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.323

GnomAD3 exomes AF: 0.320 AC: 80176 AN: 250680 Hom.: 13801 AF XY: 0.315 AC XY: 42761 AN XY: 135576

Gnomad AFR exome AF: 0.314

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.0972

Gnomad SAS exome AF: 0.221

Gnomad FIN exome AF: 0.350

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.330

GnomAD4 exome AF: 0.350 AC: 511326 AN: 1460522 Hom.: 92741 Cov.: 35 AF XY: 0.346 AC XY: 251102 AN XY: 726574

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.357

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.0932

Gnomad4 SAS exome AF: 0.221

Gnomad4 FIN exome AF: 0.352

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.338 AC: 51394 AN: 152112 Hom.: 8967 Cov.: 32 AF XY: 0.333 AC XY: 24768 AN XY: 74370

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.373

Gnomad4 ASJ AF: 0.265

Gnomad4 EAS AF: 0.0954

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.339

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.319

Alfa AF: 0.356 Hom.: 22680

Bravo AF: 0.337

TwinsUK AF: 0.363 AC: 1346

ALSPAC AF: 0.381 AC: 1470

ESP6500AA AF: 0.305 AC: 1346

ESP6500EA AF: 0.359 AC: 3088

ExAC AF: 0.318 AC: 38579

Asia WGS AF: 0.175 AC: 609 AN: 3478

EpiCase AF: 0.358

EpiControl AF: 0.356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.055
DANN	Benign	0.65
DEOGEN2	Benign	0.044	.;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.53	T;T;T;T;T
MetaRNN	Benign	0.0052	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.2	.;.;N;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.33	.;N;N;.;.
REVEL	Benign	0.031
Sift	Benign	0.086	.;T;T;.;.
Sift4G	Benign	0.081	.;T;T;.;T
Polyphen		0.0	.;B;B;.;.
Vest4		0.025, 0.024
MPC		0.014
ClinPred		0.0014	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2612086; hg19: chr18-691266; COSMIC: COSV51891957; COSMIC: COSV51891957;