chr4-158672458-T-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_004453.4(ETFDH):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,870 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 Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
ETFDH
NM_004453.4 start_lost
NM_004453.4 start_lost
Scores
6
1
5
Clinical Significance
Conservation
PhyloP100: 1.32
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.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_004453.4 (ETFDH) was described as [Pathogenic] in ClinVar as 2203581
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 4-158672458-T-C is Pathogenic according to our data. Variant chr4-158672458-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 12026.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ETFDH | NM_004453.4 | c.2T>C | p.Met1? | start_lost | 1/13 | ENST00000511912.6 | |
ETFDH | NM_001281737.2 | c.2T>C | p.Met1? | start_lost | 1/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ETFDH | ENST00000511912.6 | c.2T>C | p.Met1? | start_lost | 1/13 | 1 | NM_004453.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461870Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 727236
GnomAD4 exome
AF:
AC:
3
AN:
1461870
Hom.:
Cov.:
30
AF XY:
AC XY:
2
AN XY:
727236
Gnomad4 AFR exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Glutaric acidemia IIc Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 25, 2012 | - - |
Multiple acyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 09, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ETFDH protein in which other variant(s) (p.Pro27Ser) have been determined to be pathogenic (PMID: 3126856, 20023066, 27038534; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 12026). Disruption of the initiator codon has been observed in individuals with multiple acyl-CoA dehydrogenase deficiency (PMID: 24357026, 29336361). This sequence change affects the initiator methionine of the ETFDH mRNA. The next in-frame methionine is located at codon 62. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
A;A
PROVEAN
Pathogenic
D;N;N
REVEL
Uncertain
Polyphen
0.0
.;B;.
Vest4
0.89, 0.82
MutPred
Gain of catalytic residue at M1 (P = 0.0118);Gain of catalytic residue at M1 (P = 0.0118);Gain of catalytic residue at M1 (P = 0.0118);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at