X-72567970-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 6.47

Variant links:

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]

HDAC8 links:

ENSG00000285547 (HGNC:):

ENSG00000285547 links:

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ACMG classification

Classification made for transcript

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 link	c.356C>G	p.Thr119Arg	missense_variant	Exon 4 of 11	ENST00000373573.9	NP_060956.1	Q9BY41-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9 link	c.356C>G	p.Thr119Arg	missense_variant	Exon 4 of 11	1	NM_018486.3	ENSP00000362674.3		Q9BY41-1
ENSG00000285547	ENST00000648922.1 link	c.356C>G	p.Thr119Arg	missense_variant	Exon 4 of 12			ENSP00000497072.1		A0A3B3IRV1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cornelia de Lange syndrome 5

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Jan 30, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics, ASUI Udine	-	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

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

.;.;D;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;T;.;.;.;.

FATHMM_MKL

Pathogenic

0.98

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

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

MutationAssessor

Pathogenic

3.3

.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;M;M

PrimateAI

Uncertain

0.58

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over