X-72351759-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018486.3(HDAC8):c.1085T>C(p.Ile362Thr) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.96

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC8	NM_018486.3	c.1085T>C	p.Ile362Thr	missense_variant	10/11	ENST00000373573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC8	ENST00000373573.9	c.1085T>C	p.Ile362Thr	missense_variant	10/11	1	NM_018486.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 18, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 362 of the HDAC8 protein (p.Ile362Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HDAC8-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HDAC8 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	23
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.095	T
MutationTaster	Benign	0.94	D;D;D;D
PrimateAI	Uncertain	0.57	T
Polyphen		0.22	.;.;B;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.60, 0.69
MutPred		0.70		Loss of stability (P = 0.0189);.;Loss of stability (P = 0.0189);Loss of stability (P = 0.0189);Loss of stability (P = 0.0189);.;.;.;Loss of stability (P = 0.0189);.;Loss of stability (P = 0.0189);.;Loss of stability (P = 0.0189);.;
MVP		0.91
MPC		1.4
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.73
gMVP		0.95

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: rs2044188536; hg19: chrX-71571609;