rs398122909
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_018486.3(HDAC8):c.958G>A(p.Gly320Arg) 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).
Frequency
Genomes: not found (cov: 22)
Consequence
HDAC8
NM_018486.3 missense
NM_018486.3 missense
Scores
8
2
1
Clinical Significance
Conservation
PhyloP100: 7.48
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_018486.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.899
PP5
?
Variant X-72462051-C-T is Pathogenic according to our data. Variant chrX-72462051-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39713.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Likely_pathogenic=2, Uncertain_significance=1}. Variant chrX-72462051-C-T is described in Lovd as [Likely_pathogenic]. Variant chrX-72462051-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HDAC8 | NM_018486.3 | c.958G>A | p.Gly320Arg | missense_variant | 9/11 | ENST00000373573.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HDAC8 | ENST00000373573.9 | c.958G>A | p.Gly320Arg | missense_variant | 9/11 | 1 | NM_018486.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD4 exome Cov.: 28
GnomAD4 exome
Cov.:
28
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cornelia de Lange syndrome 5 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 13, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Apr 17, 2024 | PS4, PS3, PM1, PM2, PP3, PP5 - This missense variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID: 39713).In silico prediction tools estimated that the variant could be damaging for the protein function/stracture. It is not present in population databases (gnomAD no frequency). It is reported previously as causative (PMID: 24403048, 26671848). Functional studies support pathogenic effect (PMID: 22885700, 24403048). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2022 | This missense change has been observed in individual(s) with Cornelia de Lange syndrome or intellectual disability (PMID: 22885700, 24403048, 26671848, 27159028). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HDAC8 function (PMID: 22885700, 24403048, 26725122). 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. ClinVar contains an entry for this variant (Variation ID: 39713). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 320 of the HDAC8 protein (p.Gly320Arg). - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2017 | The p.G320R variant (also known as c.958G>A), located in coding exon 9 of the HDAC8 gene, results from a G to A substitution at nucleotide position 958. The glycine at codon 320 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified to occur de novo in two males with clinical features consistent with a diagnosis of Cornelia de Lange syndrome (CdLS); however, paternity was not confirmed (Deardorff MA et al. Nature, 2012 Sep;489:313-7; Parenti I et al. Clin. Genet., 2016 May;89:564-73). Functional studies in lymphoblastoid cell lines (LCLs) from a hemizygous male with the p.G320R variant demonstrated that this alteration results in minimal protein expression and decreased deacetylase activity (Deardorff MA et al. Nature, 2012 Sep;489:313-7; Kaiser FJ et al. Hum. Mol. Genet., 2014 Jun;23:2888-900). This alteration was also reported as de novo in a female with synophrys, micrognathia, growth delay, postnatal low weight and height, hypotonia, seizures, moderate intellectual disability with language delay, and autistic traits. Extreme X-chromosome inactivation was observed with only the wild-type allele being expressed in blood, however this may not be representative of other tissues, such as the brain (Fieremans N et al. Hum. Mutat., 2016 Aug;37:804-11). This amino acid position is highly conserved in mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 20, 2021 | Published functional studies demonstrate a damaging effect on enzyme activity (Kaiser FJ, 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32564284, 27535533, 26671848, 22885700, 30293248, 27159028, 24403048) - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Human Genetics Laboratory, State University of Rio de Janeiro | Oct 07, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | literature only | Center for Human Genetics, University of Leuven | Jan 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
Polyphen
1.0
.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.90, 0.82
MutPred
Gain of MoRF binding (P = 0.0291);.;Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);.;.;.;Gain of MoRF binding (P = 0.0291);.;Gain of MoRF binding (P = 0.0291);.;.;Gain of MoRF binding (P = 0.0291);.;Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);Gain of MoRF binding (P = 0.0291);.;
MVP
0.92
MPC
2.3
ClinPred
D
GERP RS
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