chrX-48808283-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_006044.4(HDAC6):c.763C>T(p.His255Tyr) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H255H) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )
Failed GnomAD Quality Control
Consequence
HDAC6
NM_006044.4 missense
NM_006044.4 missense
Scores
12
3
1
Clinical Significance
Conservation
PhyloP100: 5.47
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, HDAC6
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.983
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HDAC6 | NM_006044.4 | c.763C>T | p.His255Tyr | missense_variant | 10/29 | ENST00000334136.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HDAC6 | ENST00000334136.11 | c.763C>T | p.His255Tyr | missense_variant | 10/29 | 1 | NM_006044.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.14e-7 AC: 1AN: 1094563Hom.: 0 Cov.: 29 AF XY: 0.00000278 AC XY: 1AN XY: 360147
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1
AN:
1094563
Hom.:
Cov.:
29
AF XY:
AC XY:
1
AN XY:
360147
Gnomad4 AFR exome
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Gnomad4 AMR exome
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Gnomad4 ASJ exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 FIN exome
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Gnomad4 NFE exome
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Gnomad4 OTH exome
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GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2024 | The c.763C>T (p.H255Y) alteration is located in exon 10 (coding exon 9) of the HDAC6 gene. This alteration results from a C to T substitution at nucleotide position 763, causing the histidine (H) at amino acid position 255 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;D;.
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;.;.;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;.;.;.
Sift4G
Pathogenic
D;D;D;.;.;.
Polyphen
D;D;D;D;D;.
Vest4
MutPred
Loss of disorder (P = 0.0388);Loss of disorder (P = 0.0388);Loss of disorder (P = 0.0388);Loss of disorder (P = 0.0388);Loss of disorder (P = 0.0388);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.