rs1556009247

chrX-72490973-A-CchrX-72490973-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_018486.3(HDAC8):c.584T>G(p.Val195Gly) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V195D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: HDAC8 NM_018486.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.68

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 3 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-72490973-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523220.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant X-72490973-A-C is Pathogenic according to our data. Variant chrX-72490973-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 523523.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC8	NM_018486.3	c.584T>G	p.Val195Gly	missense_variant	6/11	ENST00000373573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC8	ENST00000373573.9	c.584T>G	p.Val195Gly	missense_variant	6/11	1	NM_018486.3	P4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Atrial septal defect;C0022680:Polycystic kidney disease;C1850049:Clinodactyly of the 5th finger;C3714756:Intellectual disability;C4023731:4-5 finger syndactyly;C4025871:Abnormality of the face Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	28
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;.;D;D;D;D;D;D;D;T;T;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.63, 0.53, 0.61, 0.62
MutPred		0.84		Loss of stability (P = 0.002);Loss of stability (P = 0.002);Loss of stability (P = 0.002);Loss of stability (P = 0.002);.;.;Loss of stability (P = 0.002);.;Loss of stability (P = 0.002);Loss of stability (P = 0.002);Loss of stability (P = 0.002);Loss of stability (P = 0.002);Loss of stability (P = 0.002);.;Loss of stability (P = 0.002);Loss of stability (P = 0.002);.;
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1556009247; hg19: chrX-71710823;