NM_018486.3:c.1111+6C>T

Variant names:

• chrX-72351727-G-A
• rs372334014
• NM_018486.3:c.1111+6C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_018486.3(HDAC8):​c.1111+6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000337 in 1,188,202 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 2 hem.)
• Consequence: HDAC8 NM_018486.3 splice_region, intron
• Scores: Splicing: ADA: 0.000006122
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.529

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]

ENSG00000285547 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11536071).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC8	NM_018486.3	c.1111+6C>T		splice_region_variant, intron_variant	Intron 10 of 10	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9	c.1111+6C>T		splice_region_variant, intron_variant	Intron 10 of 10	1	NM_018486.3	ENSP00000362674.3
ENSG00000285547	ENST00000648922.1	c.1111+6C>T		splice_region_variant, intron_variant	Intron 10 of 11			ENSP00000497072.1

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112602 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34738

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000111 AC: 2 AN: 179925 Hom.: 0 AF XY: 0.0000154 AC XY: 1 AN XY: 64759

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000635

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000279 AC: 3 AN: 1075600 Hom.: 0 Cov.: 26 AF XY: 0.00000581 AC XY: 2 AN XY: 344426

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00000243

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112602 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34738

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cornelia de Lange syndrome 5 Uncertain:1

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 10 of the HDAC8 gene. It does not directly change the encoded amino acid sequence of the HDAC8 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs372334014, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with HDAC8-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.0
DANN	Benign	0.55
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.22	T;T
MetaRNN	Benign	0.12	T;T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000061
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs372334014; hg19: chrX-71571577;