6-127290309-ACTCT-A

Position:

• chr6-127290309-ACTCT-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001002030.2(ECHDC1):​c.498-36_498-33delAGAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000907 in 1,434,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: ECHDC1 NM_001002030.2 intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.43

Genes affected

ECHDC1 (HGNC:21489): (ethylmalonyl-CoA decarboxylase 1) Predicted to enable carboxy-lyase activity and enoyl-CoA hydratase activity. Predicted to be involved in fatty acid beta-oxidation. Predicted to be integral component of membrane. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-127290309-ACTCT-A is Pathogenic according to our data. Variant chr6-127290309-ACTCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 978064.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ECHDC1	NM_001002030.2	c.498-36_498-33delAGAG		intron_variant		ENST00000454859.8	NP_001002030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ECHDC1	ENST00000454859.8	c.498-36_498-33delAGAG		intron_variant		1	NM_001002030.2	ENSP00000401751.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000907 AC: 13 AN: 1434042 Hom.: 0 AF XY: 0.00000702 AC XY: 5 AN XY: 712288

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000412

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000100

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of butyryl-CoA dehydrogenase Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Research Unit for Molecular Medicine, Department for Clinical Medicine, Aarhus University

Sep 12, 2019

ECHDC1 encodes a 'metabolite repair enzyme' detoxifying ethylmalonic acid (EMA), which is the biochemical hallmark of short-chain acyl-CoA dehydrogenase deficiency (OMIM:201470), caused by biallelic ACADS variants. We provide functional evidence that ECHDC1 c.498-36_498-33del4bp is a loss-of function (LOF) variant. The variant was identified in the heterozygous state together with a heterozygous ACADS NM_000017.2: c.625G>A susceptibility variant. We provide functional evidence that ECHDC1 haploinsufficiency in combination with ACADS c.625G>A susceptibility variants has a synergistic effect on cellular EMA levels. In a cohort of 82 genetically unsolved EMA patients, we found three unrelated cases with heterozygous LOF ECHDC1 variants combined with ACADS c.625G>A suceptibility variants. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		3.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs770887258; hg19: chr6-127611454;