rs121964956
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_004453.4(ETFDH):c.380T>A(p.Leu127His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,814 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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
ETFDH
NM_004453.4 missense
NM_004453.4 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 8.02
Genes affected
ETFDH (HGNC:3483): (electron transfer flavoprotein dehydrogenase) This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 4-158682399-T-A is Pathogenic according to our data. Variant chr4-158682399-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ETFDH | NM_004453.4 | c.380T>A | p.Leu127His | missense_variant | Exon 3 of 13 | ENST00000511912.6 | NP_004444.2 | |
ETFDH | NM_001281737.2 | c.239T>A | p.Leu80His | missense_variant | Exon 2 of 12 | NP_001268666.1 | ||
ETFDH | NM_001281738.1 | c.197T>A | p.Leu66His | missense_variant | Exon 1 of 11 | NP_001268667.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251414Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135898
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727210
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 18, 2022 | Variant summary: ETFDH c.380T>A (p.Leu127His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251414 control chromosomes (gnomAD). c.380T>A has been reported in the literature in multiple individuals affected with Glutaric Aciduria, Type 2c (example: Liang_2009, Wen_2010, Chien_2013, Lin_2019, Bylstra_2019 and Kuo_2021). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, no assertion criteria provided | curation | SingHealth Duke-NUS Institute of Precision Medicine | Jun 07, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 12, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu127 amino acid residue in ETFDH. Other variant(s) that disrupt this residue have been observed in individuals with ETFDH-related conditions (PMID: 19249206, 19758981, 25119904), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ETFDH protein function. ClinVar contains an entry for this variant (Variation ID: 12030). This missense change has been observed in individual(s) with multiple acyl-CoA dehydrogenase deficiency (PMID: 19249206). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121964956, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 127 of the ETFDH protein (p.Leu127His). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 20, 2024 | - - |
Glutaric acidemia IIc Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2009 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Loss of stability (P = 0.0116);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at