rs1049951

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000368547.4(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. 15/20 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
ENST00000368547.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.05

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 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, 5 uncertain in ENST00000368547.4

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 id is 379965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-133370622-G-A is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
ECHS1	NM_004092.4 linkuse as main transcript	c.224C>T	p.Thr75Ile	missense_variant	2/8	ENST00000368547.4	NP_004083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECHS1	ENST00000368547.4 linkuse as main transcript	c.224C>T	p.Thr75Ile	missense_variant	2/8	1	NM_004092.4	ENSP00000357535	P1

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

GnomAD3 exomes

AF:

0.919

AC:

228032

AN:

248164

Hom.:

106241

AF XY:

0.926

AC XY:

124624

AN XY:

134650

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 SAS exome

AF:

0.933

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

Gnomad4 AFR exome

AF:

0.519

Gnomad4 AMR exome

AF:

0.943

Gnomad4 ASJ exome

AF:

0.895

Gnomad4 EAS exome

AF:

0.976

Gnomad4 SAS exome

AF:

0.932

Gnomad4 FIN exome

AF:

0.972

Gnomad4 NFE exome

AF:

0.946

Gnomad4 OTH exome

AF:

0.913

GnomAD4 genome

AF:

0.828

AC:

126101

AN:

152296

Hom.:

54825

Cov.:

AF XY:

0.834

AC XY:

62084

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.530

Gnomad4 AMR

AF:

0.911

Gnomad4 ASJ

AF:

0.890

Gnomad4 EAS

AF:

0.979

Gnomad4 SAS

AF:

0.932

Gnomad4 FIN

AF:

0.972

Gnomad4 NFE

AF:

0.944

Gnomad4 OTH

AF:

0.865

Alfa

AF:

0.923

Hom.:

130034

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 02, 2015

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

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

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

MutationTaster

Benign

1.0

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over