10-133362874-G-C

Variant names:

• chr10-133362874-G-C
• rs1848982618
• NM_004092.4:c.867C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_004092.4(ECHS1):​c.867C>G​(p.Asp289Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D289N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ECHS1 NM_004092.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.46
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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 Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19436395).

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.867C>G	p.Asp289Glu	missense	Exon 8 of 8	NP_004083.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECHS1	ENST00000368547.4	TSL:1 MANE Select	c.867C>G	p.Asp289Glu	missense	Exon 8 of 8	ENSP00000357535.3	P30084
	ECHS1	ENST00000857570.1		c.1083C>G	p.Asp361Glu	missense	Exon 9 of 9	ENSP00000527629.1
	ECHS1	ENST00000970368.1		c.1050C>G	p.Asp350Glu	missense	Exon 9 of 9	ENSP00000640427.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.099
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.077	T
Polyphen		0.0040	B
Vest4		0.44
MutPred		0.42		Loss of MoRF binding (P = 0.0932)
MVP		0.33
MPC		0.43
ClinPred		0.94	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.70
gMVP		0.60
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs1848982618; hg19: chr10-135176378;