NM_018486.3:c.1111+131C>A

Variant names:

• chrX-72351602-G-T
• rs186172414
• NM_018486.3:c.1111+131C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_018486.3(HDAC8):​c.1111+131C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 468,597 control chromosomes in the GnomAD database, including 1 homozygotes. There are 205 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., 41 hem., cov: 23)
  • Exomes 𝑓: 0.0017 (1 hom. 164 hem.)
• Consequence: HDAC8 NM_018486.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.52
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-72351602-G-T is Benign according to our data. Variant chrX-72351602-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2660912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00118 (132/112331) while in subpopulation NFE AF = 0.0016 (85/53215). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 132 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+131C>A		intron	N/A	NP_060956.1	Q9BY41-1
	HDAC8	NM_001410725.1		c.1111+131C>A		intron	N/A	NP_001397654.1	A0A3B3IS68
	HDAC8	NM_001410727.1		c.1033+131C>A		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+131C>A		intron	N/A	ENSP00000362674.3	Q9BY41-1
	ENSG00000285547	ENST00000648922.1		c.1111+131C>A		intron	N/A	ENSP00000497072.1	A0A3B3IRV1
	HDAC8	ENST00000373568.7	TSL:5	c.1242C>A	p.Leu414Leu	synonymous	Exon 10 of 10	ENSP00000362669.3	A6NGJ7

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 132 AN: 112278 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000356

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000469

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00506

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00167 AC: 595 AN: 356266 Hom.: 1 AF XY: 0.00139 AC XY: 164 AN XY: 117740

African (AFR) AF: 0.000390 AC: 4 AN: 10265

American (AMR) AF: 0.000122 AC: 2 AN: 16360

Ashkenazi Jewish (ASJ) AF: 0.0000955 AC: 1 AN: 10476

East Asian (EAS) AF: 0.00 AC: 0 AN: 23397

South Asian (SAS) AF: 0.00 AC: 0 AN: 27410

European-Finnish (FIN) AF: 0.00446 AC: 140 AN: 31416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1476

European-Non Finnish (NFE) AF: 0.00196 AC: 421 AN: 214894

Other (OTH) AF: 0.00131 AC: 27 AN: 20572

GnomAD4 genome AF: 0.00118 AC: 132 AN: 112331 Hom.: 0 Cov.: 23 AF XY: 0.00119 AC XY: 41 AN XY: 34489

African (AFR) AF: 0.000355 AC: 11 AN: 30970

American (AMR) AF: 0.000468 AC: 5 AN: 10675

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00506 AC: 31 AN: 6125

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

European-Non Finnish (NFE) AF: 0.00160 AC: 85 AN: 53215

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000812

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
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Benign	0.66
PhyloP100		2.5
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: rs186172414; hg19: chrX-71571452;