Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate
The NM_006044.4(HDAC6):c.148G>A(p.Val50Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
HDAC6 (HGNC:14064): (histone deacetylase 6) 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 II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains which appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription. [provided by RefSeq, Jul 2008]
Verdict is Uncertain_significance. Variant got 1 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;
PP2
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PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, HDAC6
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.08310509).
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jan 18, 2023
The c.148G>A (p.V50I) alteration is located in exon 3 (coding exon 2) of the HDAC6 gene. This alteration results from a G to A substitution at nucleotide position 148, causing the valine (V) at amino acid position 50 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);