X-72567970-G-A

Position:

• chrX-72567970-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_018486.3(HDAC8):​c.356C>T​(p.Thr119Met) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T119R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 6.47

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-72567970-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 987749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant X-72567970-G-A is Pathogenic according to our data. Variant chrX-72567970-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC8	NM_018486.3	c.356C>T	p.Thr119Met	missense_variant	4/11	ENST00000373573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC8	ENST00000373573.9	c.356C>T	p.Thr119Met	missense_variant	4/11	1	NM_018486.3	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 06, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 119 of the HDAC8 protein (p.Thr119Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Cornelia de Lange syndrome or Say-Barber-Biesecker-Young-Simpson syndrome (PMID: 24375697, 25574841). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 92043). 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 expected to disrupt HDAC8 protein function. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Oct 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2019	Variant summary: HDAC8 c.356C>T (p.Thr119Met) results in a non-conservative amino acid change located in the Histone deacetylase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 182900 control chromosomes (gnomAD). c.356C>T has been reported in the literature in individuals affected with Cornelia de Lange syndrome 5 (Yuan_2015, Salzberg_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories submitted pathogenic classifications for this variant to ClinVar (last evaluated in 2013 and 2014, respectively). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University	Dec 18, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 19, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Dec 02, 2014	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	.;.;D;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Pathogenic	3.3	.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.2	.;.;D;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;.;D;N;.;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;.;D;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;.;D;T;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.72, 0.72, 0.72, 0.83, 0.81, 0.80
MutPred		0.82		Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);.;Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);.;Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);Loss of catalytic residue at T119 (P = 0.0213);
MVP		0.92
MPC		2.2
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

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: rs587779380; hg19: chrX-71787820; COSMIC: COSV101002336; COSMIC: COSV101002336;