rs752317877
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000182.5(HADHA):c.955G>A(p.Gly319Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000495 in 1,596,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G319G) has been classified as Likely benign.
Frequency
Consequence
NM_000182.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HADHA | NM_000182.5 | c.955G>A | p.Gly319Ser | missense_variant | 10/20 | ENST00000380649.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HADHA | ENST00000380649.8 | c.955G>A | p.Gly319Ser | missense_variant | 10/20 | 1 | NM_000182.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251414Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135866
GnomAD4 exome AF: 0.0000519 AC: 75AN: 1444156Hom.: 0 Cov.: 26 AF XY: 0.0000542 AC XY: 39AN XY: 719750
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74272
ClinVar
Submissions by phenotype
Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Pathogenic:1Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 18, 2023 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 2016 | A variant of uncertain significance has also been identified in the HADHA gene. The G319S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G319S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G319S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | HADHA: PM2 - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2017 | - - |
Mitochondrial trifunctional protein deficiency Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Children's Medical Center, Molecular Pathology and Cytogenetics Lab, Tehran University of Medical Sciences | - | For this missense variant, computational prediction tools unanimously support a deleterious effect on the gene and the frequency of this variant is extremely low in gnomAD population databases. - |
Mitochondrial trifunctional protein deficiency;C3711645:Long chain 3-hydroxyacyl-CoA dehydrogenase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2021 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 319 of the HADHA protein (p.Gly319Ser). This variant is present in population databases (rs752317877, gnomAD 0.006%). This missense change has been observed in individual(s) with peripheral neuropathy (PMID: 30682426). ClinVar contains an entry for this variant (Variation ID: 203743). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at