Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5
The NM_018486.3(HDAC8):c.416G>C(p.Gly139Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G139R) has been classified as Likely pathogenic.
HDAC8 (HGNC:13315): (histone deacetylase 8) Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alters chromosome structure and affects transcription factor access to DNA. The protein encoded by this gene belongs to class I of the histone deacetylase family. It catalyzes the deacetylation of lysine residues in the histone N-terminal tails and represses transcription in large multiprotein complexes with transcriptional co-repressors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PM5
?
PM5 - Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Other missense variant is known to change same aminoacid residue: Variant chrX-72567911-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1064767.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.95
PP5
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant X-72567910-C-G is Pathogenic according to our data. Variant chrX-72567910-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235479.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);.;Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);.;Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);Loss of glycosylation at S138 (P = 0.0803);