rs72630048

Variant names:

• chrX-72495283-G-A
• rs72630048
• NM_018486.3:c.438-15C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_018486.3(HDAC8):​c.438-15C>T variant causes a 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 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.79
• 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: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Cornelia de Lange syndrome 5

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285547 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.438-15C>T		intron_variant	Intron 4 of 10	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.438-15C>T		intron_variant	Intron 4 of 10	1	NM_018486.3	ENSP00000362674.3
ENSG00000285547	ENST00000648922.1	c.438-15C>T		intron_variant	Intron 4 of 11			ENSP00000497072.1

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 7076 AN: 111199 Hom.: 854 Cov.: 22

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

GnomAD2 exomes AF: 0.141 AC: 23113 AN: 164484 AF XY: 0.128

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 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

African (AFR) AF: 0.0496 AC: 1219 AN: 24560

American (AMR) AF: 0.315 AC: 10835 AN: 34375

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 603 AN: 18716

East Asian (EAS) AF: 0.770 AC: 22670 AN: 29460

South Asian (SAS) AF: 0.209 AC: 10613 AN: 50884

European-Finnish (FIN) AF: 0.0313 AC: 1237 AN: 39551

Middle Eastern (MID) AF: 0.0202 AC: 79 AN: 3915

European-Non Finnish (NFE) AF: 0.00355 AC: 2719 AN: 766641

Other (OTH) AF: 0.0692 AC: 2993 AN: 43224

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

African (AFR) AF: 0.0498 AC: 1526 AN: 30670

American (AMR) AF: 0.177 AC: 1852 AN: 10449

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 93 AN: 2645

East Asian (EAS) AF: 0.725 AC: 2494 AN: 3442

South Asian (SAS) AF: 0.217 AC: 571 AN: 2630

European-Finnish (FIN) AF: 0.0281 AC: 168 AN: 5979

Middle Eastern (MID) AF: 0.00926 AC: 2 AN: 216

European-Non Finnish (NFE) AF: 0.00500 AC: 265 AN: 53022

Other (OTH) AF: 0.0702 AC: 106 AN: 1511

Alfa AF: 0.0332 Hom.: 1717

Bravo AF: 0.0847

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 22, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cornelia de Lange syndrome 5 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.81
PhyloP100		1.8
PromoterAI		0.0077	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs72630048; hg19: chrX-71715133; COSMIC: COSV65238138;