10-133362587-G-T

Variant names:

• chr10-133362587-G-T
• rs4604
• NM_004092.4:c.*281C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004092.4(ECHS1):​c.*281C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ECHS1 NM_004092.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• 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: Ambry Genetics, ClinGen, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECHS1	NM_004092.4	MANE Select	c.*281C>A		3_prime_UTR	Exon 8 of 8	NP_004083.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ECHS1	ENST00000368547.4	TSL:1 MANE Select	c.*281C>A		3_prime_UTR	Exon 8 of 8	ENSP00000357535.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 342316 Hom.: 0 Cov.: 2 AF XY: 0.00 AC XY: 0 AN XY: 179776

African (AFR) AF: 0.00 AC: 0 AN: 10008

American (AMR) AF: 0.00 AC: 0 AN: 13974

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10554

East Asian (EAS) AF: 0.00 AC: 0 AN: 22584

South Asian (SAS) AF: 0.00 AC: 0 AN: 37854

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1482

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 205092

Other (OTH) AF: 0.00 AC: 0 AN: 19730

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.17
DANN	Benign	0.66
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs4604; hg19: chr10-135176091;