rs1553316176
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000182.5(HADHA):c.72del(p.Tyr24Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,506 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y24Y) has been classified as Likely benign.
Frequency
Consequence
NM_000182.5 frameshift
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 |
---|---|---|---|---|---|---|---|
HADHA | NM_000182.5 | c.72del | p.Tyr24Ter | frameshift_variant | 2/20 | ENST00000380649.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.72del | p.Tyr24Ter | frameshift_variant | 2/20 | 1 | NM_000182.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251002Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135778
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1448506Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3AN XY: 721582
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2018 | Variant summary: HADHA c.72delT (p.Tyr24X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. p.R291X and p.L656X). The variant allele was found at a frequency of 4.1e-06 in 246080 control chromosomes in gnomAD, which does not exceed the maximal expected allele frequency for a pathogenic variant in HADHA. The variant c.72delT has been reported in the literature in individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (SPIEKERKOETTER_2004). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined here, the variant was classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | HADHA: PVS1, PM2, PM3:Supporting, PS4:Supporting - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2021 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552438). This premature translational stop signal has been observed in individual(s) with mitochondrial trifunctional protein deficiency (PMID: 14630990). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr24*) in the HADHA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at