rs397515416

Variant names:

• chrX-72495167-T-C
• rs397515416
• NM_018486.3:c.539A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_018486.3(HDAC8):​c.539A>G​(p.His180Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.52

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity HDAC8_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant X-72495167-T-C is Pathogenic according to our data. Variant chrX-72495167-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 39711.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-72495167-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.539A>G	p.His180Arg	missense_variant	Exon 5 of 11	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.539A>G	p.His180Arg	missense_variant	Exon 5 of 11	1	NM_018486.3	ENSP00000362674.3
ENSG00000285547	ENST00000648922.1	c.539A>G	p.His180Arg	missense_variant	Exon 5 of 12			ENSP00000497072.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cornelia de Lange syndrome 5 Pathogenic:1

Sep 13, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;H;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.7	.;.;D;.;.;.;D;.;.;.;.;D;.;.;.;D;.;D;.;.;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;.;.;.;.;D;.;.;.;D;.;D;.;.;D;.
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;D;.;.;.;.;.;.;.;.;D;.;D;.;.;D;.
Polyphen		1.0	.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.98, 0.97, 0.98, 0.95
MutPred		0.96		Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);.;.;Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);.;Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);Gain of MoRF binding (P = 0.0826);.;.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
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: rs397515416; hg19: chrX-71715017;