X-72351715-TC-T

Variant names:

• chrX-72351715-TC-T
• rs1440186821
• NM_018486.3:c.1111+17delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018486.3(HDAC8):​c.1111+17delG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,045,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000032 (0 hom. 7 hem.)
• Consequence: HDAC8 NM_018486.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.88
• 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 -10 ACMG points.

• BP6: Variant X-72351715-TC-T is Benign according to our data. Variant chrX-72351715-TC-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2416617.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000316 (33/1045227) while in subpopulation NFE AF = 0.0000415 (33/794976). AF 95% confidence interval is 0.0000296. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 33 XL,AD gene.

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.1111+17delG		intron	N/A	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.1111+17delG		intron	N/A	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410727.1		c.1033+17delG		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.1111+17delG		intron	N/A	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.1111+17delG		intron	N/A	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000373568.7	TSL:5	c.1128delG	p.Arg377GlyfsTer28	frameshift	Exon 10 of 10	ENSP00000362669.3	A6NGJ7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000171 AC: 3 AN: 174969 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000257

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.0000316 AC: 33 AN: 1045227 Hom.: 0 Cov.: 22 AF XY: 0.0000217 AC XY: 7 AN XY: 322757

African (AFR) AF: 0.00 AC: 0 AN: 25383

American (AMR) AF: 0.00 AC: 0 AN: 34898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19014

East Asian (EAS) AF: 0.00 AC: 0 AN: 29932

South Asian (SAS) AF: 0.00 AC: 0 AN: 52342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3973

European-Non Finnish (NFE) AF: 0.0000415 AC: 33 AN: 794976

Other (OTH) AF: 0.00 AC: 0 AN: 44339

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cornelia de Lange syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.9

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: rs1440186821; hg19: chrX-71571565;