rs397515415

Positions:

• chrX-72495216-G-A
• chrX-72495216-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018486.3(HDAC8):​c.490C>T​(p.Arg164*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HDAC8 NM_018486.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.79

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]

ENSG00000285547 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-72495216-G-A is Pathogenic according to our data. Variant chrX-72495216-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 39710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-72495216-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.490C>T	p.Arg164*	stop_gained	5/11	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.490C>T	p.Arg164*	stop_gained	5/11	1	NM_018486.3	ENSP00000362674.3
ENSG00000285547	ENST00000648922.1	c.490C>T	p.Arg164*	stop_gained	5/12			ENSP00000497072.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	May 08, 2019	This nonsense variant found in exon 5 of 11 is predicted to result in loss of normal protein function. This variant has been previously reported as a de novo change in patients with Cornelia de Lange syndrome (PMID: 22885700). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.490C>T (p.Arg164Ter) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 19, 2014	This variant has been previously reported as disease-causing and was found once in our laboratory de novo in a 21-year-old female with autism, intellectual disability, hypotonia, hyperextensibility, cardiomyopathy, scoliosis, dysautonomia -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Nov 10, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2017

The R164X variant in the HDAC8 gene has been reported previously as heterozygous de novo in a female with Cornelia de Lange syndrome who exhibited growth delays, absent speech, dysmorphic facial features, asymmetric skull, limb length discrepancy and dysplastic kidneys (Deardorff et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R164X variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R164X as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.79	D
Vest4		0.94, 0.93, 0.94, 0.94, 0.94
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397515415; hg19: chrX-71715066; COSMIC: COSV65238373;