chr2-26277115-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3PP5
The NM_000183.3(HADHB):āc.397A>Gā(p.Thr133Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,607,024 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T133P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000183.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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HADHB | NM_000183.3 | c.397A>G | p.Thr133Ala | missense_variant | Exon 7 of 16 | ENST00000317799.10 | NP_000174.1 | |
HADHB | NM_001281512.2 | c.352A>G | p.Thr118Ala | missense_variant | Exon 6 of 15 | NP_001268441.1 | ||
HADHB | NM_001281513.2 | c.331A>G | p.Thr111Ala | missense_variant | Exon 8 of 17 | NP_001268442.1 | ||
HADHB | XM_011532803.2 | c.397A>G | p.Thr133Ala | missense_variant | Exon 7 of 16 | XP_011531105.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000921 AC: 14AN: 151942Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000111 AC: 28AN: 251430Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135896
GnomAD4 exome AF: 0.000199 AC: 289AN: 1455082Hom.: 1 Cov.: 28 AF XY: 0.000197 AC XY: 143AN XY: 724400
GnomAD4 genome AF: 0.0000921 AC: 14AN: 151942Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7AN XY: 74216
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Saleh2022[paper], 35403730, 35383965) -
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HADHB: PM2, PM3, PP3 -
Mitochondrial trifunctional protein deficiency 2 Pathogenic:2
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PS3_Moderate, PM1, PM3, PM5_Supporting, PP3 -
Mitochondrial trifunctional protein deficiency Pathogenic:1Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 133 of the HADHB protein (p.Thr133Ala). This variant is present in population databases (rs371159065, gnomAD 0.02%). This missense change has been observed in individual(s) with and/or HADHB-related conditions (PMID: 35383965, 35403730). ClinVar contains an entry for this variant (Variation ID: 235337). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HADHB protein function. For these reasons, this variant has been classified as Pathogenic. -
Mitochondrial trifunctional protein deficiency 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at