NM_018486.3:c.932C>T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_018486.3(HDAC8):c.932C>T(p.Thr311Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_018486.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HDAC8 | ENST00000373573.9 | c.932C>T | p.Thr311Met | missense_variant | Exon 9 of 11 | 1 | NM_018486.3 | ENSP00000362674.3 | ||
ENSG00000285547 | ENST00000648922.1 | c.932C>T | p.Thr311Met | missense_variant | Exon 9 of 12 | ENSP00000497072.1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 exomes AF: 0.00000546 AC: 1AN: 183129Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67597
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1093642Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 359132
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 5 Pathogenic:3
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This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 311 of the HDAC8 protein (p.Thr311Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 22885700, 30158690; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 39712). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HDAC8 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HDAC8 function (PMID: 22885700). For these reasons, this variant has been classified as Pathogenic. -
Inborn genetic diseases Pathogenic:1
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not provided Pathogenic:1
Published functional studies demonstrate a damaging effect, resulting in reduced enzyme activity (Deardorff et al., 2012; Decroos et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22885700, 25075551, 30158690, 24403048, 31216405) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at