rs1556165162

Positions:

• chrX-72572656-TGG-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_018486.3(HDAC8):​c.104_105del​(p.Pro35GlnfsTer11) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 17)
• Consequence: HDAC8 NM_018486.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant X-72572656-TGG-T is Pathogenic according to our data. Variant chrX-72572656-TGG-T is described in ClinVar as [Pathogenic]. Clinvar id is 545414.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC8	NM_018486.3	c.104_105del	p.Pro35GlnfsTer11	frameshift_variant	1/11	ENST00000373573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC8	ENST00000373573.9	c.104_105del	p.Pro35GlnfsTer11	frameshift_variant	1/11	1	NM_018486.3	P4

Frequencies

GnomAD3 genomes Cov.: 17

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 17

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Medical Genetics Lab, Policlinico S. Orsola.Malpighi

May 03, 2018

This is a predicted null variant (frameshift) in a gene (HDAC8) where loss of function is a known cause of disease. It is absent from large population databases. No other family members were affected and the variant is likely de novo in this female patient (absent in her father, sister and maternal grandomother; her mother died due to accidental causes). Mutations in HDAC8 are a known cause of Cornelia de Lange syndrome type 5 and Intellectual Disability; clinical features of this patient are consistent with those previously described in patients with HDAC8 mutations. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556165162; hg19: chrX-71792506;