rs398124151
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004453.4(ETFDH):c.1234G>T(p.Glu412Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,609,352 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_004453.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ETFDH | NM_004453.4 | c.1234G>T | p.Glu412Ter | stop_gained | 10/13 | ENST00000511912.6 | |
ETFDH | NM_001281737.2 | c.1093G>T | p.Glu365Ter | stop_gained | 9/12 | ||
ETFDH | NM_001281738.1 | c.1051G>T | p.Glu351Ter | stop_gained | 8/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ETFDH | ENST00000511912.6 | c.1234G>T | p.Glu412Ter | stop_gained | 10/13 | 1 | NM_004453.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251160Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135768
GnomAD4 exome AF: 0.0000460 AC: 67AN: 1457186Hom.: 0 Cov.: 28 AF XY: 0.0000510 AC XY: 37AN XY: 725292
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
ClinVar
Submissions by phenotype
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 29, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2023 | This sequence change creates a premature translational stop signal (p.Glu412*) in the ETFDH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ETFDH are known to be pathogenic (PMID: 16510302, 23785301). This variant is present in population databases (rs398124151, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with glutaric aciduria type 2 (Invitae). ClinVar contains an entry for this variant (Variation ID: 95071). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 20, 2023 | Observed in the heterozygous state, or with a second ETFDH variant, in multiple patients with features of multiple acyl-CoA dehydrogenase deficiency who were tested at GeneDx or reported in the published literature (Dillon et al., 2018; van Rijt et al., 2020); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31904027, 29453417) - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 20, 2012 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at