chrX-72572083-TTCAA-T

Position:

• chrX-72572083-TTCAA-T

Variant summary

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

The ENST00000373573.9(HDAC8):​c.134_137del​(p.Ile45LysfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I45I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 21)
• Consequence: HDAC8 ENST00000373573.9 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 8.34

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 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-72572083-TTCAA-T is Pathogenic according to our data. Variant chrX-72572083-TTCAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 211139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-72572083-TTCAA-T is described in Lovd as [Pathogenic]. Variant chrX-72572083-TTCAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.134_137del	p.Ile45LysfsTer9	frameshift_variant	2/11	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.134_137del	p.Ile45LysfsTer9	frameshift_variant	2/11	1	NM_018486.3	ENSP00000362674	P4

Frequencies

GnomAD3 genomes Cov.: 21

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

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 04, 2019	A heterozygous frameshift deletion variant, NM_018486.3(HDAC8):c.134_137del, has been identified in exon 2 of 11 of the HDAC8 gene. This deletion is predicted to create a frameshift starting at amino acid position 45, introducing a stop codon 9 residues downstream (NM_018486.3(HDAC8):p.(Ile45Lysfs*9)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is absent in population databases (gnomAD, dbSNP, 1000G). The variant has been previously described as pathogenic (ClinVar). Several truncating variants downstream predicted to result in NMD have been reported pathogenic in patients with Cornelia de Lange syndrome (ClinVar, Decipher). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 23, 2014	- -

Computational scores

Source: dbNSFP v4.3

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: rs797045610; hg19: chrX-71791933;