X-72567970-G-C

Variant names:

• chrX-72567970-G-C
• rs587779380
• NM_018486.3:c.356C>G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_018486.3(HDAC8):​c.356C>G​(p.Thr119Arg) 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 (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

ENSG00000285547 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant X-72567970-G-C is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.356C>G	p.Thr119Arg	missense_variant	Exon 4 of 11	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.356C>G	p.Thr119Arg	missense_variant	Exon 4 of 11	1	NM_018486.3	ENSP00000362674.3
ENSG00000285547	ENST00000648922.1	c.356C>G	p.Thr119Arg	missense_variant	Exon 4 of 12			ENSP00000497072.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:2

Jan 30, 2019

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 4 of the HDAC8 gene that results in the amino acid substitution of Arginine for Threonine at codon 119 was detected. The observed variant c.356C>G(p.Thr119Arg) not been reported in the 1000 genomes, ExAC and our internal databases. The in silico prediction of the variant is probably damaging by PolyPhen-2 (HumDiv), damaging by SIFT, damaging by LRT and MutationTaster2. The reference codon is conserved across species. Segregation analysis suggests the variant to be of de novo origin. In summary, the variant meets our criteria to be classified as pathogenic. -

-

Institute of Medical Genetics, ASUI Udine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HDAC c.356C>G results in a non-conservative amino acid change (p.Thr119Arg) located in the Histone deacetylase domain of the encoded protein sequence. The variant is classified as pathogenic, since it is absent in population databases, it is predicted as having a deleterious effect by multiple computational analyses and it is a de novo variant. Moreover, a c.356C>T transition has been described (Yuan et al., 2015) and two clinical diagnostic laboratories submitted pathogenic classifications for this variant to ClinVar. To date, 48 unique deleterious variants have been reported in HDAC8 and associated to Cornelia de Lange syndrome 5. By molecular modeling, the amino acid change compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, triggering global structural changes that propagate through the protein scaffold to the catalytic site, creating de facto haploinsufficiency. The effects observed are similar of those described by Decroos and colleagues regarding the p.Gly117Glu replacement, which compromises the conformational flexibility of the HDAC8 loop required for optimal catalytic function, resulting in a 5% residual enzyme activity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;D;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	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	0.96	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
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.3	.;.;D;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;.;D;N;.;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	.;.;D;.;.;.;.;.;.;.;.;D;.;.;D;.;D;.;.;D;D;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;T;.;.;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.83, 0.83, 0.83, 0.89, 0.88, 0.88
MutPred		0.84		Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);.;Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);.;Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);Gain of methylation at T119 (P = 0.0107);
MVP		0.98
MPC		2.3
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		1.0

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;