18-674324-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017512.7(ENOSF1):c.1313T>G(p.Leu438Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ENOSF1 NM_017512.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.120387316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENOSF1	NM_017512.7	c.1313T>G	p.Leu438Arg	missense_variant	16/16	ENST00000647584.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENOSF1	ENST00000647584.2	c.1313T>G	p.Leu438Arg	missense_variant	16/16		NM_017512.7	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248090 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458566 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000760

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.1334T>G (p.L445R) alteration is located in exon 15 (coding exon 15) of the ENOSF1 gene. This alteration results from a T to G substitution at nucleotide position 1334, causing the leucine (L) at amino acid position 445 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.81	T;T;T;T;T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.98	N;N;N;N;N;N
PrimateAI	Benign	0.40	T
Polyphen		0.0040, 0.0	.;B;B;.;.
Vest4		0.60, 0.56, 0.58
MutPred		0.40		.;.;Gain of MoRF binding (P = 2e-04);.;.;
MVP		0.42
MPC		0.018
ClinPred		0.24	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs750805379; hg19: chr18-674324;