10-133373332-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PS1_ModeratePS3PM2PP5_Moderate

The NM_004092.4(ECHS1):c.2T>C(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 (★). ClinVar reports functional evidence for this variant: "SCV002937071: Studies have shown that disruption of the initiator codon alters ECHS1 gene expression (PMID:25393721).".

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

ECHS1
NM_004092.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.09

Publications

5 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
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: Pathogenic. The variant received 18 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 30 pathogenic variants. Next in-frame start position is after 103 codons. Genomic position: 133370011. Lost 0.352 part of the original CDS.

PS1

Another start lost variant in NM_004092.4 (ECHS1) was described as [Likely_pathogenic] in ClinVar

PS3

PS3 evidence extracted from ClinVar submissions: SCV002937071: Studies have shown that disruption of the initiator codon alters ECHS1 gene expression (PMID: 25393721).

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 VariationId is 1903474.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004092.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECHS1	NM_004092.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	NP_004083.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ECHS1	ENST00000368547.4	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 8	ENSP00000357535.3	P30084
ECHS1	ENST00000857570.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 9	ENSP00000527629.1
ECHS1	ENST00000970368.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 9	ENSP00000640427.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000102

AC:

AN:

98504

AF XY:

0.0000182

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:

0.0000288

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1350402

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

666216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27742

American (AMR)

AF:

0.00

AC:

AN:

32772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23756

East Asian (EAS)

AF:

0.0000997

AC:

AN:

30100

South Asian (SAS)

AF:

0.00

AC:

AN:

76760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34424

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4472

European-Non Finnish (NFE)

AF:

0.0000320

AC:

AN:

1064016

Other (OTH)

AF:

0.0000177

AC:

AN:

56360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.019

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.90

PhyloP100

1.1

PROVEAN

Benign

-1.2

REVEL

Benign

0.28

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.91

Vest4

0.53

MutPred

0.65

Gain of catalytic residue at M1 (P = 0.0101)

MVP

0.62

ClinPred

0.53

GERP RS

2.6

PromoterAI

-0.81

Under-expression

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.83

gMVP

0.80

Mutation Taster

=10/190

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over