rs398122888
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_018486.3(HDAC8):c.164+5G>A variant causes a splice donor 5th base, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 21)
Consequence
HDAC8
NM_018486.3 splice_donor_5th_base, intron
NM_018486.3 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9841
2
Clinical Significance
Conservation
PhyloP100: 6.61
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
PP5
?
Variant X-72572052-C-T is Pathogenic according to our data. Variant chrX-72572052-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37252.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-72572052-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HDAC8 | NM_018486.3 | c.164+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000373573.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HDAC8 | ENST00000373573.9 | c.164+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_018486.3 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 21
GnomAD3 genomes
?
Cov.:
21
GnomAD4 exome Cov.: 26
GnomAD4 exome
Cov.:
26
GnomAD4 genome ? Cov.: 21
GnomAD4 genome
?
Cov.:
21
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
HDAC8-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 02, 2023 | The HDAC8 c.164+5G>A variant is predicted to interfere with splicing. This variant was reported in the hemizygous state in seven males from a single family with X-linked intellectual disability, truncal obesity, gynecomastia, hypogonadism and craniofacial deformities. Carrier females were more mildly affected and exhibited skewed X-inactivation. RNA studies in patient lymphocytes showed this variant resulted in skipping of exon 2 and premature termination (Harakalova. 2012. PubMed ID: 22889856). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in HDAC8 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cornelia de Lange syndrome 5 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2012 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at