chr1-8861413-C-T

Position:

• chr1-8861413-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001428.5(ENO1):​c.1252G>A​(p.Gly418Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENO1 NM_001428.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79

Genes affected

ENO1 (HGNC:3350): (enolase 1) This gene encodes alpha-enolase, one of three enolase isoenzymes found in mammals. Each isoenzyme is a homodimer composed of 2 alpha, 2 gamma, or 2 beta subunits, and functions as a glycolytic enzyme. Alpha-enolase in addition, functions as a structural lens protein (tau-crystallin) in the monomeric form. Alternative splicing of this gene results in a shorter isoform that has been shown to bind to the c-myc promoter and function as a tumor suppressor. Several pseudogenes have been identified, including one on the long arm of chromosome 1. Alpha-enolase has also been identified as an autoantigen in Hashimoto encephalopathy. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENO1	NM_001428.5	c.1252G>A	p.Gly418Ser	missense_variant	12/12	ENST00000234590.10	NP_001419.1
ENO1	NM_001353346.3	c.1252G>A	p.Gly418Ser	missense_variant	12/12		NP_001340275.1
ENO1	NM_001201483.4	c.973G>A	p.Gly325Ser	missense_variant	11/11		NP_001188412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENO1	ENST00000234590.10	c.1252G>A	p.Gly418Ser	missense_variant	12/12	1	NM_001428.5	ENSP00000234590	P3
ENO1	ENST00000464920.2	n.2137G>A		non_coding_transcript_exon_variant	9/9	1
ENO1	ENST00000647408.1	c.1252G>A	p.Gly418Ser	missense_variant	12/12			ENSP00000495530	A1
ENO1	ENST00000646370.2	c.*1005G>A		3_prime_UTR_variant, NMD_transcript_variant	13/13			ENSP00000495568

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Sep 26, 2023

The c.1252G>A (p.G418S) alteration is located in exon 12 (coding exon 11) of the ENO1 gene. This alteration results from a G to A substitution at nucleotide position 1252, causing the glycine (G) at amino acid position 418 to be replaced by a serine (S). 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	0.26
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.033	D
MutationAssessor	Pathogenic	3.7	H;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.9	D;.;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0040	D;.;.
Polyphen		0.99	D;D;.
Vest4		0.75
MutPred		0.63		Gain of phosphorylation at G418 (P = 0.0333);Gain of phosphorylation at G418 (P = 0.0333);Gain of phosphorylation at G418 (P = 0.0333);
MVP		0.91
MPC		0.97
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-8921472;