18-691266-A-G

Variant names:

• chr18-691266-A-G
• rs2612086
• NM_017512.7:c.434T>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.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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 40 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]

ACMG classification

Our verdict: Benign. The variant received -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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOSF1	NM_017512.7	MANE Select	c.434T>C	p.Met145Thr	missense	Exon 6 of 16	NP_059982.2
	ENOSF1	NM_001354067.2		c.578T>C	p.Met193Thr	missense	Exon 6 of 16	NP_001340996.1
	ENOSF1	NM_202758.5		c.578T>C	p.Met193Thr	missense	Exon 6 of 15	NP_974487.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENOSF1	ENST00000647584.2	MANE Select	c.434T>C	p.Met145Thr	missense	Exon 6 of 16	ENSP00000497230.2
	ENOSF1	ENST00000383578.7	TSL:1	c.188T>C	p.Met63Thr	missense	Exon 5 of 16	ENSP00000373072.3
	ENOSF1	ENST00000581475.5	TSL:1	n.424-521T>C		intron	N/A	ENSP00000464614.1

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

GnomAD2 exomes AF: 0.320 AC: 80176 AN: 250680 AF XY: 0.315

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 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

African (AFR) AF: 0.313 AC: 10482 AN: 33456

American (AMR) AF: 0.357 AC: 15962 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 7265 AN: 26126

East Asian (EAS) AF: 0.0932 AC: 3697 AN: 39682

South Asian (SAS) AF: 0.221 AC: 19008 AN: 86182

European-Finnish (FIN) AF: 0.352 AC: 18773 AN: 53388

Middle Eastern (MID) AF: 0.248 AC: 1427 AN: 5764

European-Non Finnish (NFE) AF: 0.373 AC: 414867 AN: 1110916

Other (OTH) AF: 0.329 AC: 19845 AN: 60334

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

African (AFR) AF: 0.316 AC: 13121 AN: 41504

American (AMR) AF: 0.373 AC: 5693 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 921 AN: 3470

East Asian (EAS) AF: 0.0954 AC: 494 AN: 5178

South Asian (SAS) AF: 0.219 AC: 1054 AN: 4816

European-Finnish (FIN) AF: 0.339 AC: 3595 AN: 10590

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.372 AC: 25256 AN: 67960

Other (OTH) AF: 0.319 AC: 674 AN: 2112

Alfa AF: 0.354 Hom.: 44946

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 v4.9

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
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.2	N
PhyloP100		-0.022
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.031
Sift	Benign	0.086	T
Sift4G	Benign	0.081	T
Polyphen		0.0	B
Vest4		0.025
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
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs2612086; hg19: chr18-691266; COSMIC: COSV51891957; COSMIC: COSV51891957;