chr1-8866297-T-C

Position:

• chr1-8866297-T-C

Variant summary

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

The NM_001428.5(ENO1):​c.649A>G​(p.Ile217Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENO1 NM_001428.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.98

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENO1	NM_001428.5	c.649A>G	p.Ile217Val	missense_variant	7/12	ENST00000234590.10	NP_001419.1
ENO1	NM_001353346.3	c.649A>G	p.Ile217Val	missense_variant	7/12		NP_001340275.1
ENO1	NM_001201483.4	c.370A>G	p.Ile124Val	missense_variant	6/11		NP_001188412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENO1	ENST00000234590.10	c.649A>G	p.Ile217Val	missense_variant	7/12	1	NM_001428.5	ENSP00000234590.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 07, 2023

The c.649A>G (p.I217V) alteration is located in exon 7 (coding exon 6) of the ENO1 gene. This alteration results from a A to G substitution at nucleotide position 649, causing the isoleucine (I) at amino acid position 217 to be replaced by a valine (V). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.4	M;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.84	N;.;.
REVEL	Benign	0.28
Sift	Benign	0.063	T;.;.
Sift4G	Benign	0.18	T;.;.
Polyphen		0.0010	B;B;.
Vest4		0.60
MutPred		0.63		Gain of ubiquitination at K221 (P = 0.115);Gain of ubiquitination at K221 (P = 0.115);Gain of ubiquitination at K221 (P = 0.115);
MVP		0.76
MPC		0.26
ClinPred		0.88	D
GERP RS		5.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.9
Varity_R		0.66
gMVP		0.57

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: rs772567946; hg19: chr1-8926356;