rs112196218
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Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_000182.5(HADHA):c.573+8_573+9insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,606,826 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0056 ( 7 hom., cov: 32)
Exomes 𝑓: 0.00097 ( 11 hom. )
Consequence
HADHA
NM_000182.5 intron
NM_000182.5 intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.557
Genes affected
HADHA (HGNC:4801): (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids. The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. Mutations in this gene result in trifunctional protein deficiency or LCHAD deficiency. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -16 ACMG points.
BP6
?
Variant 2-26232151-T-TA is Benign according to our data. Variant chr2-26232151-T-TA is described in ClinVar as [Benign]. Clinvar id is 203737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00557 (848/152272) while in subpopulation AFR AF= 0.0191 (793/41548). AF 95% confidence interval is 0.018. There are 7 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 7 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HADHA | NM_000182.5 | c.573+8_573+9insT | intron_variant | ENST00000380649.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.573+8_573+9insT | intron_variant | 1 | NM_000182.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00555 AC: 845AN: 152154Hom.: 7 Cov.: 32
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GnomAD3 exomes AF: 0.00229 AC: 575AN: 251216Hom.: 5 AF XY: 0.00221 AC XY: 300AN XY: 135770
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GnomAD4 exome AF: 0.000973 AC: 1415AN: 1454554Hom.: 11 Cov.: 29 AF XY: 0.00110 AC XY: 795AN XY: 724208
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GnomAD4 genome ? AF: 0.00557 AC: 848AN: 152272Hom.: 7 Cov.: 32 AF XY: 0.00527 AC XY: 392AN XY: 74450
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 12, 2018 | Variant summary: HADHA c.573+8dupT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant changes to splicing, however, these predictions have not been assessed by functional studies. The variant allele was found at a frequency of 0.0026 in 276958 control chromosomes in the gnomAD database, including 8 homozygotes. The observed variant frequency is approximately 1.36 fold above the estimated maximal expected allele frequency for a pathogenic variant in HADHA causing Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency phenotype (0.0019), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.573+8dupT in individuals affected with Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 08, 2014 | The variant is found in FAO-MET,UCD-MET panel(s). - |
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Benign:1
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 22, 2023 | - - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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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