10-133373332-A-G
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_004092.4(ECHS1):āc.2T>Cā(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,502,432 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 Pathogenic (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Exomes š: 0.000028 ( 0 hom. )
Consequence
ECHS1
NM_004092.4 start_lost
NM_004092.4 start_lost
Scores
4
2
10
Clinical Significance
Conservation
PhyloP100: 1.09
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_004092.4 (ECHS1) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 10-133373332-A-G is Pathogenic according to our data. Variant chr10-133373332-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1903474.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ECHS1 | NM_004092.4 | c.2T>C | p.Met1? | start_lost | 1/8 | ENST00000368547.4 | NP_004083.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ECHS1 | ENST00000368547.4 | c.2T>C | p.Met1? | start_lost | 1/8 | 1 | NM_004092.4 | ENSP00000357535.3 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152030Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000102 AC: 1AN: 98504Hom.: 0 AF XY: 0.0000182 AC XY: 1AN XY: 54898
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GnomAD4 exome AF: 0.0000281 AC: 38AN: 1350402Hom.: 0 Cov.: 34 AF XY: 0.0000270 AC XY: 18AN XY: 666216
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152030Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74262
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 11, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ECHS1 protein in which other variant(s) (p.Ala2Val) have been determined to be pathogenic (PMID: 25393721, 32677908, 33139125, 33163364). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that disruption of the initiator codon alters ECHS1 gene expression (PMID: 25393721). ClinVar contains an entry for this variant (Variation ID: 1903474). Disruption of the initiator codon has been observed in individual(s) with Leigh syndrome (PMID: 25393721). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the ECHS1 mRNA. The next in-frame methionine is located at codon 103. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0101);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at