NM_018486.3:c.490C>T

Variant names:

• chrX-72495216-G-A
• rs397515415
• NM_018486.3:c.490C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018486.3(HDAC8):​c.490C>T​(p.Arg164*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HDAC8 NM_018486.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.79
• Publications: 8 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-72495216-G-A is Pathogenic according to our data. Variant chrX-72495216-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 39710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.490C>T	p.Arg164*	stop_gained	Exon 5 of 11	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.490C>T	p.Arg164*	stop_gained	Exon 5 of 12	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410727.1		c.490C>T	p.Arg164*	stop_gained	Exon 5 of 10	NP_001397656.1	A6NFW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC8	ENST00000373573.9	TSL:1 MANE Select	c.490C>T	p.Arg164*	stop_gained	Exon 5 of 11	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.490C>T	p.Arg164*	stop_gained	Exon 5 of 12	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000412342.6	TSL:1	n.*188C>T		non_coding_transcript_exon	Exon 4 of 7	ENSP00000400180.1	F8WCG4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Cornelia de Lange syndrome 5 (4)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.79	D
PhyloP100		3.8
Vest4		0.94
GERP RS		5.2
PromoterAI		-0.067	Neutral
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397515415; hg19: chrX-71715066; COSMIC: COSV65238373;