rs782459830

Variant names:

• chrX-72330702-G-A
• rs782459830
• NM_018486.3:c.1112-626C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001410725.1(HDAC8):​c.1178C>T​(p.Thr393Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 110,639 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 8/9 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HDAC8 NM_001410725.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.38
• Publications: 0 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: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Cornelia de Lange syndrome 5

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

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000285547 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03954655).
• BP6: Variant X-72330702-G-A is Benign according to our data. Variant chrX-72330702-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2660911.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000226 (25/110639) while in subpopulation AFR AF = 0.000559 (17/30399). AF 95% confidence interval is 0.000356. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410725.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC8	NM_018486.3	MANE Select	c.1112-626C>T		intron	N/A	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.1178C>T	p.Thr393Met	missense	Exon 11 of 12	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410728.1		c.905C>T	p.Thr302Met	missense	Exon 9 of 10	NP_001397657.1	A0A3B3IT30

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC8	ENST00000373573.9	TSL:1 MANE Select	c.1112-626C>T		intron	N/A	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.1111+21031C>T		intron	N/A	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000648452.1		c.1178C>T	p.Thr393Met	missense	Exon 11 of 12	ENSP00000497268.1	A0A3B3ISJ4

Frequencies

GnomAD3 genomes AF: 0.000226 AC: 25 AN: 110586 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000389

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.000677

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 119 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 35

African (AFR) AF: 0.00 AC: 0 AN: 3

American (AMR) AF: 0.00 AC: 0 AN: 10

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 95

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.000226 AC: 25 AN: 110639 Hom.: 0 Cov.: 22 AF XY: 0.000213 AC XY: 7 AN XY: 32873

African (AFR) AF: 0.000559 AC: 17 AN: 30399

American (AMR) AF: 0.00 AC: 0 AN: 10297

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3515

South Asian (SAS) AF: 0.000390 AC: 1 AN: 2564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 52975

Other (OTH) AF: 0.000668 AC: 1 AN: 1497

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.000249

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.095
DANN	Benign	0.74
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.040	T
PhyloP100		-2.4
GERP RS		-5.8
Mutation Taster		=100/0	polymorphism

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: rs782459830; hg19: chrX-71550552;