rs797045612

Positions:

• chrX-72491001-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The ENST00000373573.9(HDAC8):​c.556G>A​(p.Glu186Lys) variant causes a missense 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 Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E186E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HDAC8 ENST00000373573.9 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.69

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.

• PM1: In a helix (size 5) in uniprot entity HDAC8_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000373573.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.465
• PP5: Variant X-72491001-C-T is Pathogenic according to our data. Variant chrX-72491001-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 211142.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.556G>A	p.Glu186Lys	missense_variant	6/11	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.556G>A	p.Glu186Lys	missense_variant	6/11	1	NM_018486.3	ENSP00000362674	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 14, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.83	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
ClinPred		1.0	D
GERP RS		4.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs797045612; hg19: chrX-71710851;