NM_018486.3:c.159G>A

Variant names:

• chrX-72572062-C-T
• rs11093377
• NM_018486.3:c.159G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_018486.3(HDAC8):​c.159G>A​(p.Gln53Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0825 in 1,186,704 control chromosomes in the GnomAD database, including 17,200 homozygotes. There are 30,181 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5302 hom., 7181 hem., cov: 21)
  • Exomes 𝑓: 0.067 (11898 hom. 23000 hem.)
• Consequence: HDAC8 NM_018486.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.990
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-72572062-C-T is Benign according to our data. Variant chrX-72572062-C-T is described in ClinVar as Benign. ClinVar VariationId is 158659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.99 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.159G>A	p.Gln53Gln	synonymous_variant	Exon 2 of 11	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.159G>A	p.Gln53Gln	synonymous_variant	Exon 2 of 11	1	NM_018486.3	ENSP00000362674.3
ENSG00000285547	ENST00000648922.1	c.159G>A	p.Gln53Gln	synonymous_variant	Exon 2 of 12			ENSP00000497072.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 25548 AN: 109860 Hom.: 5299 Cov.: 21

Gnomad AFR AF: 0.625

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.0315

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.0215

Gnomad MID AF: 0.0847

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.212

GnomAD2 exomes AF: 0.182 AC: 27603 AN: 151775 AF XY: 0.125

Gnomad AFR exome AF: 0.631

Gnomad AMR exome AF: 0.403

Gnomad ASJ exome AF: 0.0260

Gnomad EAS exome AF: 0.674

Gnomad FIN exome AF: 0.0249

Gnomad NFE exome AF: 0.00930

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.0671 AC: 72282 AN: 1076797 Hom.: 11898 Cov.: 27 AF XY: 0.0662 AC XY: 23000 AN XY: 347671

African (AFR) AF: 0.645 AC: 16111 AN: 24965

American (AMR) AF: 0.392 AC: 12392 AN: 31607

Ashkenazi Jewish (ASJ) AF: 0.0291 AC: 551 AN: 18907

East Asian (EAS) AF: 0.684 AC: 20113 AN: 29418

South Asian (SAS) AF: 0.207 AC: 10403 AN: 50241

European-Finnish (FIN) AF: 0.0269 AC: 1077 AN: 40102

Middle Eastern (MID) AF: 0.0701 AC: 284 AN: 4054

European-Non Finnish (NFE) AF: 0.00759 AC: 6320 AN: 832299

Other (OTH) AF: 0.111 AC: 5031 AN: 45204

GnomAD4 genome AF: 0.233 AC: 25590 AN: 109907 Hom.: 5302 Cov.: 21 AF XY: 0.223 AC XY: 7181 AN XY: 32243

African (AFR) AF: 0.625 AC: 18661 AN: 29860

American (AMR) AF: 0.288 AC: 2976 AN: 10334

Ashkenazi Jewish (ASJ) AF: 0.0315 AC: 83 AN: 2636

East Asian (EAS) AF: 0.674 AC: 2317 AN: 3439

South Asian (SAS) AF: 0.215 AC: 544 AN: 2526

European-Finnish (FIN) AF: 0.0215 AC: 124 AN: 5773

Middle Eastern (MID) AF: 0.0930 AC: 20 AN: 215

European-Non Finnish (NFE) AF: 0.0103 AC: 545 AN: 52940

Other (OTH) AF: 0.213 AC: 320 AN: 1502

Alfa AF: 0.115 Hom.: 2013

Bravo AF: 0.282

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Sep 26, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cornelia de Lange syndrome 5 Benign:2

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

May 26, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.6
DANN	Benign	0.54
PhyloP100		0.99
Mutation Taster		=298/2	polymorphism (auto)

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: rs11093377; hg19: chrX-71791912; COSMIC: COSV65227624;