rs377656387
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong
The NM_004453.4(ETFDH):c.1448C>A(p.Pro483Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P483L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004453.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ETFDH | NM_004453.4 | c.1448C>A | p.Pro483Gln | missense_variant | 11/13 | ENST00000511912.6 | NP_004444.2 | |
ETFDH | NM_001281737.2 | c.1307C>A | p.Pro436Gln | missense_variant | 10/12 | NP_001268666.1 | ||
ETFDH | NM_001281738.1 | c.1265C>A | p.Pro422Gln | missense_variant | 9/11 | NP_001268667.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ETFDH | ENST00000511912.6 | c.1448C>A | p.Pro483Gln | missense_variant | 11/13 | 1 | NM_004453.4 | ENSP00000426638 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 14, 2024 | Variant summary: ETFDH c.1448C>A (p.Pro483Gln) 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 was absent in 251258 control chromosomes. c.1448C>A has been reported in the literature in at least one compound heterozygous individual affected with late-onset Glutaric Aciduria, Type 2 (e.g. Zhu_2023). These data are not sufficient alone to allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant located at the same codon (c.1448C>T, p.Pro483Leu) has been classified as pathogenic, supporting a critical relevance of this residue to ETFDH protein function. The following publication has been ascertained in the context of this evaluation (PMID: 36779069). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at