rs1057516460
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_ModeratePM2PP3PP5_Very_Strong
The NM_000182.5(HADHA):c.1086-3_1092del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
HADHA
NM_000182.5 splice_acceptor, coding_sequence, intron
NM_000182.5 splice_acceptor, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
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 Pathogenic. Variant got 13 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05846422 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.1, offset of 23, new splice context is: cttggctattcttggtgcAGggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant 2-26204189-CCAGATGCCTG-C is Pathogenic according to our data. Variant chr2-26204189-CCAGATGCCTG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HADHA | NM_000182.5 | c.1086-3_1092del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 12/20 | ENST00000380649.8 | ||
GAREM2 | XM_011532567.4 | c.*1873_*1882del | 3_prime_UTR_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.1086-3_1092del | splice_acceptor_variant, coding_sequence_variant, intron_variant | 12/20 | 1 | NM_000182.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461604Hom.: 0 AF XY: 0.00000413 AC XY: 3AN XY: 727126
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 06, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 02, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 18, 2021 | - - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 27, 2023 | This variant results in the deletion of part of exon 12 (c.1086-3_1092del) of the HADHA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HADHA are known to be pathogenic (PMID: 7738175, 21103935, 21549624, 22459206). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (PMID: 10352164). This variant is also known as delta-4 -> 091. ClinVar contains an entry for this variant (Variation ID: 370400). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at