rs72630048

Variant names:

• chrX-72495283-G-A
• rs72630048
• NM_018486.3:c.438-15C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_018486.3(HDAC8):​c.438-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0535 in 1,122,577 control chromosomes in the GnomAD database, including 9,177 homozygotes. There are 20,953 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (849 hom., 2353 hem., cov: 22)
  • Exomes 𝑓: 0.052 (8328 hom. 18600 hem.)
• Consequence: HDAC8 NM_018486.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.79
• Publications: 5 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant X-72495283-G-A is Benign according to our data. Variant chrX-72495283-G-A is described in ClinVar as Benign. ClinVar VariationId is 158662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 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.438-15C>T		intron	N/A	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.438-15C>T		intron	N/A	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410727.1		c.438-15C>T		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.438-15C>T		intron	N/A	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.438-15C>T		intron	N/A	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000412342.6	TSL:1	n.*136-15C>T		intron	N/A	ENSP00000400180.1	F8WCG4

Frequencies

GnomAD3 genomes AF: 0.0636 AC: 7076 AN: 111199 Hom.: 854 Cov.: 22

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.0281

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.0670

GnomAD2 exomes AF: 0.141 AC: 23113 AN: 164484 AF XY: 0.128

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.0299

Gnomad EAS exome AF: 0.736

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.00540

Gnomad OTH exome AF: 0.0908

GnomAD4 exome AF: 0.0524 AC: 52968 AN: 1011326 Hom.: 8328 Cov.: 20 AF XY: 0.0636 AC XY: 18600 AN XY: 292506

African (AFR) AF: 0.0496 AC: 1219 AN: 24560

American (AMR) AF: 0.315 AC: 10835 AN: 34375

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 603 AN: 18716

East Asian (EAS) AF: 0.770 AC: 22670 AN: 29460

South Asian (SAS) AF: 0.209 AC: 10613 AN: 50884

European-Finnish (FIN) AF: 0.0313 AC: 1237 AN: 39551

Middle Eastern (MID) AF: 0.0202 AC: 79 AN: 3915

European-Non Finnish (NFE) AF: 0.00355 AC: 2719 AN: 766641

Other (OTH) AF: 0.0692 AC: 2993 AN: 43224

GnomAD4 genome AF: 0.0636 AC: 7077 AN: 111251 Hom.: 849 Cov.: 22 AF XY: 0.0702 AC XY: 2353 AN XY: 33497

African (AFR) AF: 0.0498 AC: 1526 AN: 30670

American (AMR) AF: 0.177 AC: 1852 AN: 10449

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 93 AN: 2645

East Asian (EAS) AF: 0.725 AC: 2494 AN: 3442

South Asian (SAS) AF: 0.217 AC: 571 AN: 2630

European-Finnish (FIN) AF: 0.0281 AC: 168 AN: 5979

Middle Eastern (MID) AF: 0.00926 AC: 2 AN: 216

European-Non Finnish (NFE) AF: 0.00500 AC: 265 AN: 53022

Other (OTH) AF: 0.0702 AC: 106 AN: 1511

Alfa AF: 0.0332 Hom.: 1717

Bravo AF: 0.0847

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Cornelia de Lange syndrome 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.81
PhyloP100		1.8
PromoterAI		0.0077	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs72630048; hg19: chrX-71715133; COSMIC: COSV65238138;