rs797045612

Variant names:

• chrX-72491001-C-T
• rs797045612
• NM_018486.3:c.556G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_018486.3(HDAC8):​c.556G>A​(p.Glu186Lys) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E186A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.69
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Cornelia de Lange syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Cornelia de Lange syndrome 5

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Wilson-Turner syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285547 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_018486.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: REVEL computational evidence supports a deleterious effect, 0.83
• PP5: Variant X-72491001-C-T is Pathogenic according to our data. Variant chrX-72491001-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 211142.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018486.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC8	NM_018486.3	MANE Select	c.556G>A	p.Glu186Lys	missense	Exon 6 of 11	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.556G>A	p.Glu186Lys	missense	Exon 6 of 12	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410728.1		c.283G>A	p.Glu95Lys	missense	Exon 4 of 10	NP_001397657.1	A0A3B3IT30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC8	ENST00000373573.9	TSL:1 MANE Select	c.556G>A	p.Glu186Lys	missense	Exon 6 of 11	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.556G>A	p.Glu186Lys	missense	Exon 6 of 12	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000412342.6	TSL:1	n.*254G>A		non_coding_transcript_exon	Exon 5 of 7	ENSP00000400180.1	F8WCG4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Cornelia de Lange syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.83	D
PhyloP100		3.7
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797045612; hg19: chrX-71710851;