rs397515417

chrX-72462077-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PP3_Moderate PP5_Very_Strong

The NM_018486.3(HDAC8):c.932C>T(p.Thr311Met) variant causes a missense change. 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. T311T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.30

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 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_018486.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant X-72462077-G-A is Pathogenic according to our data. Variant chrX-72462077-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-72462077-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC8	NM_018486.3	c.932C>T	p.Thr311Met	missense_variant	9/11	ENST00000373573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC8	ENST00000373573.9	c.932C>T	p.Thr311Met	missense_variant	9/11	1	NM_018486.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183129 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67597

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1093642 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 359132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 08, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 13, 2012	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 08, 2022	Experimental studies have shown that this missense change affects HDAC8 function (PMID: 22885700). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 39712). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 22885700, 30158690). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 311 of the HDAC8 protein (p.Thr311Met). -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2015

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2022

Published functional studies demonstrate a damaging effect, resulting in reduced enzyme activity (Deardorff et al., 2012; Decroos et al., 2014); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22885700, 25075551, 30158690, 24403048, 31216405) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	26
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.013	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.86, 0.78
MutPred		0.83		Gain of catalytic residue at T311 (P = 0.1959);.;Gain of catalytic residue at T311 (P = 0.1959);Gain of catalytic residue at T311 (P = 0.1959);Gain of catalytic residue at T311 (P = 0.1959);.;.;.;Gain of catalytic residue at T311 (P = 0.1959);.;Gain of catalytic residue at T311 (P = 0.1959);.;.;Gain of catalytic residue at T311 (P = 0.1959);.;Gain of catalytic residue at T311 (P = 0.1959);Gain of catalytic residue at T311 (P = 0.1959);Gain of catalytic residue at T311 (P = 0.1959);.;
MVP		0.98
MPC		2.2
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.75
gMVP		0.91

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: rs397515417; hg19: chrX-71681927; COSMIC: COSV65265074; COSMIC: COSV65265074;