chr17-44083837-T-G
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2
The NM_005474.5(HDAC5):c.2323A>C(p.Met775Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000227 in 1,513,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000062 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00024 ( 0 hom. )
Consequence
HDAC5
NM_005474.5 missense
NM_005474.5 missense
Scores
1
1
15
Clinical Significance
Conservation
PhyloP100: 5.84
Genes affected
HDAC5 (HGNC:14068): (histone deacetylase 5) 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 the class II histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. It coimmunoprecipitates only with HDAC3 family member and might form multicomplex proteins. It also interacts with myocyte enhancer factor-2 (MEF2) proteins, resulting in repression of MEF2-dependent genes. This gene is thought to be associated with colon cancer. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, HDAC5
BP4
?
Computational evidence support a benign effect (MetaRNN=0.20791745).
BS2
?
High AC in GnomAd at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HDAC5 | NM_005474.5 | c.2323A>C | p.Met775Leu | missense_variant | 17/27 | ENST00000682912.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HDAC5 | ENST00000682912.1 | c.2323A>C | p.Met775Leu | missense_variant | 17/27 | NM_005474.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000624 AC: 9AN: 144270Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251358Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135888
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GnomAD4 exome AF: 0.000245 AC: 335AN: 1368906Hom.: 0 Cov.: 34 AF XY: 0.000246 AC XY: 167AN XY: 679814
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GnomAD4 genome ? AF: 0.0000624 AC: 9AN: 144270Hom.: 0 Cov.: 32 AF XY: 0.0000713 AC XY: 5AN XY: 70102
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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 | Dec 20, 2023 | The c.2326A>C (p.M776L) alteration is located in exon 17 (coding exon 16) of the HDAC5 gene. This alteration results from a A to C substitution at nucleotide position 2326, causing the methionine (M) at amino acid position 776 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Benign
Sift
Benign
T;T;.
Sift4G
Benign
T;T;T
Polyphen
B;B;B
Vest4
MutPred
0.63
.;.;Gain of ubiquitination at K774 (P = 0.0982);
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at