1-8866398-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001428.5(ENO1):​c.548G>A​(p.Arg183His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,614,104 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ENO1
NM_001428.5 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.87
Variant links:
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]
MIR6728 (HGNC:49961): (microRNA 6728) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.796

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ENO1NM_001428.5 linkc.548G>A p.Arg183His missense_variant Exon 7 of 12 ENST00000234590.10 NP_001419.1 P06733-1A0A024R4F1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENO1ENST00000234590.10 linkc.548G>A p.Arg183His missense_variant Exon 7 of 12 1 NM_001428.5 ENSP00000234590.4 P06733-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152216
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251490
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000615
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461888
Hom.:
0
Cov.:
32
AF XY:
0.0000261
AC XY:
19
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152216
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 11, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.548G>A (p.R183H) alteration is located in exon 7 (coding exon 6) of the ENO1 gene. This alteration results from a G to A substitution at nucleotide position 548, causing the arginine (R) at amino acid position 183 to be replaced by a histidine (H). 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
0.24
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.22
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
D;D;.;T
Eigen
Uncertain
0.30
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.89
.;D;D;D
M_CAP
Benign
0.028
D
MetaRNN
Pathogenic
0.80
D;D;D;D
MetaSVM
Benign
-0.66
T
MutationAssessor
Pathogenic
3.3
M;M;.;.
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-3.6
D;.;.;.
REVEL
Uncertain
0.43
Sift
Uncertain
0.013
D;.;.;.
Sift4G
Benign
0.065
T;.;.;T
Polyphen
0.042
B;B;.;.
Vest4
0.85
MutPred
0.64
Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);
MVP
0.86
MPC
0.37
ClinPred
0.65
D
GERP RS
5.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.64
gMVP
0.78

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs779265966; hg19: chr1-8926457; COSMIC: COSV52305736; COSMIC: COSV52305736; API