rs141407224
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_004453.4(ETFDH):c.679C>A(p.Pro227Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000154 in 1,554,770 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 Likely pathogenic (★★).
Frequency
Consequence
NM_004453.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ETFDH | NM_004453.4 | c.679C>A | p.Pro227Thr | missense_variant | Exon 6 of 13 | ENST00000511912.6 | NP_004444.2 | |
ETFDH | NM_001281737.2 | c.538C>A | p.Pro180Thr | missense_variant | Exon 5 of 12 | NP_001268666.1 | ||
ETFDH | NM_001281738.1 | c.496C>A | p.Pro166Thr | missense_variant | Exon 4 of 11 | NP_001268667.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151978Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251428Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135888
GnomAD4 exome AF: 0.0000164 AC: 23AN: 1402792Hom.: 0 Cov.: 24 AF XY: 0.0000200 AC XY: 14AN XY: 701394
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151978Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 74216
ClinVar
Submissions by phenotype
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:3Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 227 of the ETFDH protein (p.Pro227Thr). This variant is present in population databases (rs141407224, gnomAD 0.006%). This missense change has been observed in individuals with glutaric aciduria (PMID: 34066864; internal data). ClinVar contains an entry for this variant (Variation ID: 459966). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ETFDH protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
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The variant has been reported pathogenic (PS1, Ali et al. 2021, PMID: 34066864). The variant causes functional damage (PS3, clinical/biochemical evidence). The variant is rare in the healthy population (PM2 - supporting). The variant is homozygous (PM3-supporting according to the ClinGen Sequence variant interpretation Recommendation for in-trans Criterion (PM3) - Version 1.0) -
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not provided Pathogenic:1
ETFDH: PM2, PM3, PM5, PP4:Moderate -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at