X-72330118-T-C

Variant names:

• chrX-72330118-T-C
• rs2984288
• NM_018486.3:c.1112-42A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018486.3(HDAC8):​c.1112-42A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00358 in 1,078,302 control chromosomes in the GnomAD database, including 92 homozygotes. There are 1,043 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (46 hom., 554 hem., cov: 22)
  • Exomes 𝑓: 0.0019 (46 hom. 489 hem.)
• Consequence: HDAC8 NM_018486.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-72330118-T-C is Benign according to our data. Variant chrX-72330118-T-C is described in ClinVar as Benign. ClinVar VariationId is 1270507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018486.3. 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.1112-42A>G		intron	N/A	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.1190-42A>G		intron	N/A	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410727.1		c.1034-42A>G		intron	N/A	NP_001397656.1	A6NFW1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC8	ENST00000373573.9	TSL:1 MANE Select	c.1112-42A>G		intron	N/A	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.1111+21615A>G		intron	N/A	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000647859.1		c.*748A>G		3_prime_UTR	Exon 11 of 11	ENSP00000497530.1	A0A3B3IRI9

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 1991 AN: 112014 Hom.: 46 Cov.: 22

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00808

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.00545 AC: 952 AN: 174680 AF XY: 0.00375

Gnomad AFR exome AF: 0.0657

Gnomad AMR exome AF: 0.00346

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000633

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.00194 AC: 1872 AN: 966233 Hom.: 46 Cov.: 20 AF XY: 0.00186 AC XY: 489 AN XY: 263553

African (AFR) AF: 0.0615 AC: 1481 AN: 24070

American (AMR) AF: 0.00375 AC: 130 AN: 34621

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18451

East Asian (EAS) AF: 0.00 AC: 0 AN: 29676

South Asian (SAS) AF: 0.0000795 AC: 4 AN: 50303

European-Finnish (FIN) AF: 0.0000495 AC: 2 AN: 40368

Middle Eastern (MID) AF: 0.00105 AC: 4 AN: 3819

European-Non Finnish (NFE) AF: 0.0000622 AC: 45 AN: 723139

Other (OTH) AF: 0.00493 AC: 206 AN: 41786

GnomAD4 genome AF: 0.0177 AC: 1988 AN: 112069 Hom.: 46 Cov.: 22 AF XY: 0.0162 AC XY: 554 AN XY: 34227

African (AFR) AF: 0.0609 AC: 1875 AN: 30804

American (AMR) AF: 0.00798 AC: 84 AN: 10532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3583

South Asian (SAS) AF: 0.00 AC: 0 AN: 2682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6109

Middle Eastern (MID) AF: 0.0183 AC: 4 AN: 218

European-Non Finnish (NFE) AF: 0.000169 AC: 9 AN: 53288

Other (OTH) AF: 0.0105 AC: 16 AN: 1522

Alfa AF: 0.00643 Hom.: 206

Bravo AF: 0.0202

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		1.1
Mutation Taster		=100/0	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: rs2984288; hg19: chrX-71549968;