rs72630048

chrX-72495283-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_018486.3(HDAC8):c.438-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,122,577 control chromosomes in the GnomAD database, including 9,177 homozygotes. There are 20,953 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (849 hom., 2353 hem., cov: 22)
  • Exomes 𝑓: 0.052 (8328 hom. 18600 hem.)
• Consequence: HDAC8 NM_018486.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.79

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant X-72495283-G-A is Benign according to our data. Variant chrX-72495283-G-A is described in ClinVar as [Benign]. Clinvar id is 158662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC8	NM_018486.3	c.438-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000373573.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC8	ENST00000373573.9	c.438-15C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_018486.3	P4

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 7076 AN: 111199 Hom.: 854 Cov.: 22 AF XY: 0.0704 AC XY: 2353 AN XY: 33435

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.0670

GnomAD3 exomes AF: 0.141 AC: 23113 AN: 164484 Hom.: 3981 AF XY: 0.128 AC XY: 6655 AN XY: 52048

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.736

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.0908

GnomAD4 exome AF: 0.0524 AC: 52968 AN: 1011326 Hom.: 8328 Cov.: 20 AF XY: 0.0636 AC XY: 18600 AN XY: 292506

Gnomad4 AFR exome AF: 0.0496

Gnomad4 AMR exome AF: 0.315

Gnomad4 ASJ exome AF: 0.0322

Gnomad4 EAS exome AF: 0.770

Gnomad4 SAS exome AF: 0.209

Gnomad4 FIN exome AF: 0.0313

Gnomad4 NFE exome AF: 0.00355

Gnomad4 OTH exome AF: 0.0692

GnomAD4 genome AF: 0.0636 AC: 7077 AN: 111251 Hom.: 849 Cov.: 22 AF XY: 0.0702 AC XY: 2353 AN XY: 33497

Gnomad4 AFR AF: 0.0498

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.0352

Gnomad4 EAS AF: 0.725

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.0281

Gnomad4 NFE AF: 0.00500

Gnomad4 OTH AF: 0.0702

Alfa AF: 0.0316 Hom.: 1547

Bravo AF: 0.0847

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cornelia de Lange syndrome 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	17
Dann	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72630048; hg19: chrX-71715133; COSMIC: COSV65238138;