10-133362895-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_004092.4(ECHS1):​c.846G>C​(p.Lys282Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,824 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 (★). Synonymous variant affecting the same amino acid position (i.e. K282K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ECHS1
NM_004092.4 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.97
Variant links:
Genes affected
ECHS1 (HGNC:3151): (enoyl-CoA hydratase, short chain 1) The protein encoded by this gene functions in the second step of the mitochondrial fatty acid beta-oxidation pathway. It catalyzes the hydration of 2-trans-enoyl-coenzyme A (CoA) intermediates to L-3-hydroxyacyl-CoAs. The gene product is a member of the hydratase/isomerase superfamily. It localizes to the mitochondrial matrix. Transcript variants utilizing alternative transcription initiation sites have been described in the literature. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_004092.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 35 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8627 (below the threshold of 3.09). Trascript score misZ: 0.70218 (below the threshold of 3.09). GenCC associations: The gene is linked to mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency, Leigh syndrome, Leigh syndrome with leukodystrophy.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ECHS1NM_004092.4 linkc.846G>C p.Lys282Asn missense_variant Exon 8 of 8 ENST00000368547.4 NP_004083.3 P30084

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ECHS1ENST00000368547.4 linkc.846G>C p.Lys282Asn missense_variant Exon 8 of 8 1 NM_004092.4 ENSP00000357535.3 P30084

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251460
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461824
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727194
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
AC:
2
AN:
33480
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44724
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26136
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39700
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86258
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53360
Gnomad4 NFE exome
AF:
0.00000270
AC:
3
AN:
1112008
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
60390
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000113

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jan 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 282 of the ECHS1 protein (p.Lys282Asn). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ECHS1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ECHS1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Uncertain
0.013
T
BayesDel_noAF
Benign
-0.22
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Benign
0.041
D
MetaRNN
Pathogenic
0.84
D
MetaSVM
Benign
-0.35
T
MutationAssessor
Pathogenic
3.3
M
PrimateAI
Uncertain
0.69
T
PROVEAN
Pathogenic
-4.7
D
REVEL
Uncertain
0.44
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0060
D
Polyphen
1.0
D
Vest4
0.81
MutPred
0.61
Loss of methylation at K282 (P = 0.0027);
MVP
0.80
MPC
1.4
ClinPred
1.0
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.92
gMVP
0.91
Mutation Taster
=24/76
disease causing

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: rs781373718; hg19: chr10-135176399; COSMIC: COSV99529496; COSMIC: COSV99529496; API