NM_004092.4:c.224C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1

The NM_004092.4(ECHS1):c.224C>T(p.Thr75Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.924 in 1,612,138 control chromosomes in the GnomAD database, including 695,367 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T75S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.83 ( 54825 hom., cov: 35)

Exomes 𝑓: 0.93 ( 640542 hom. )

Consequence

ECHS1
NM_004092.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.05

Publications

40 publications found

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]

ECHS1 Gene-Disease associations (from GenCC):

Leigh syndrome
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
Leigh syndrome with leukodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ECHS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_004092.4

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 Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=7.3618094E-7).

BP6

Variant 10-133370622-G-A is Benign according to our data. Variant chr10-133370622-G-A is described in ClinVar as Benign. ClinVar VariationId is 379965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ECHS1	NM_004092.4 link	c.224C>T	p.Thr75Ile	missense_variant	Exon 2 of 8	ENST00000368547.4	NP_004083.3	P30084

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ECHS1	ENST00000368547.4 link	c.224C>T	p.Thr75Ile	missense_variant	Exon 2 of 8	1	NM_004092.4	ENSP00000357535.3		P30084

Frequencies

GnomAD3 genomes

AF:

0.828

AC:

126054

AN:

152178

Hom.:

54810

Cov.:

show subpopulations

Gnomad AFR

AF:

0.531

Gnomad AMI

AF:

0.897

Gnomad AMR

AF:

0.911

Gnomad ASJ

AF:

0.890

Gnomad EAS

AF:

0.979

Gnomad SAS

AF:

0.931

Gnomad FIN

AF:

0.972

Gnomad MID

AF:

0.883

Gnomad NFE

AF:

0.944

Gnomad OTH

AF:

0.864

GnomAD2 exomes

AF:

0.919

AC:

228032

AN:

248164

AF XY:

0.926

show subpopulations

Gnomad AFR exome

AF:

0.517

Gnomad AMR exome

AF:

0.946

Gnomad ASJ exome

AF:

0.893

Gnomad EAS exome

AF:

0.975

Gnomad FIN exome

AF:

0.973

Gnomad NFE exome

AF:

0.946

Gnomad OTH exome

AF:

0.927

GnomAD4 exome

AF:

0.934

AC:

1363915

AN:

1459842

Hom.:

640542

Cov.:

AF XY:

0.935

AC XY:

679258

AN XY:

726128

show subpopulations

African (AFR)

AF:

0.519

AC:

17348

AN:

33446

American (AMR)

AF:

0.943

AC:

42018

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

23346

AN:

26088

East Asian (EAS)

AF:

0.976

AC:

38722

AN:

39670

South Asian (SAS)

AF:

0.932

AC:

80214

AN:

86066

European-Finnish (FIN)

AF:

0.972

AC:

50972

AN:

52440

Middle Eastern (MID)

AF:

0.889

AC:

5127

AN:

5764

European-Non Finnish (NFE)

AF:

0.946

AC:

1051080

AN:

1111468

Other (OTH)

AF:

0.913

AC:

55088

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

4771

9542

14313

19084

23855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21538

43076

64614

86152

107690

<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

AF:

0.828

AC:

126101

AN:

152296

Hom.:

54825

Cov.:

AF XY:

0.834

AC XY:

62084

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.530

AC:

22013

AN:

41514

American (AMR)

AF:

0.911

AC:

13951

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.890

AC:

3091

AN:

3472

East Asian (EAS)

AF:

0.979

AC:

5070

AN:

5178

South Asian (SAS)

AF:

0.932

AC:

4503

AN:

4832

European-Finnish (FIN)

AF:

0.972

AC:

10325

AN:

10626

Middle Eastern (MID)

AF:

0.878

AC:

258

AN:

294

European-Non Finnish (NFE)

AF:

0.944

AC:

64241

AN:

68042

Other (OTH)

AF:

0.865

AC:

1831

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

857

1715

2572

3430

4287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.910

Hom.:

255498

Bravo

AF:

0.809

TwinsUK

AF:

0.938

AC:

3478

ALSPAC

AF:

0.944

AC:

3640

ESP6500AA

AF:

0.530

AC:

2335

ESP6500EA

AF:

0.940

AC:

8084

ExAC

AF:

0.910

AC:

110057

Asia WGS

AF:

0.930

AC:

3233

AN:

3478

EpiCase

AF:

0.943

EpiControl

AF:

0.942

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 02, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.075

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.67

MetaRNN

Benign

7.4e-7

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.99

PhyloP100

1.1

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.1

REVEL

Benign

0.097

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

0.040

Vest4

0.033

MPC

0.49

ClinPred

0.0073

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.046

gMVP

0.48

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over