4-107989926-CCA-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PVS1PM2BP6_Moderate
The ENST00000505878.4(HADH):c.175_176del(p.Thr59HisfsTer71) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
HADH
ENST00000505878.4 frameshift
ENST00000505878.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.367
Genes affected
HADH (HGNC:4799): (hydroxyacyl-CoA dehydrogenase) This gene is a member of the 3-hydroxyacyl-CoA dehydrogenase gene family. The encoded protein functions in the mitochondrial matrix to catalyze the oxidation of straight-chain 3-hydroxyacyl-CoAs as part of the beta-oxidation pathway. Its enzymatic activity is highest with medium-chain-length fatty acids. Mutations in this gene cause one form of familial hyperinsulinemic hypoglycemia. The human genome contains a related pseudogene of this gene on chromosome 15. [provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
BP6
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Variant 4-107989926-CCA-C is Benign according to our data. Variant chr4-107989926-CCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 3036274.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HADH | NM_005327.7 | c.-3_-2del | 5_prime_UTR_variant | 1/8 | ENST00000309522.8 | ||
HADH | NM_001184705.4 | c.-3_-2del | 5_prime_UTR_variant | 1/9 | |||
HADH | XR_007096395.1 | n.42_43del | non_coding_transcript_exon_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADH | ENST00000309522.8 | c.-3_-2del | 5_prime_UTR_variant | 1/8 | 1 | NM_005327.7 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000452 AC: 11AN: 243394Hom.: 0 AF XY: 0.0000528 AC XY: 7AN XY: 132472
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GnomAD4 exome AF: 0.0000164 AC: 24AN: 1459700Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 726094
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ClinVar
Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
HADH-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 25, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at