Genetic Variant HDAC8:n.-5G>A (chrX-72572766-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The ENST00000412342.6(HDAC8):n.-5G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000417 in 1,197,628 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 21)

Exomes 𝑓: 0.000043 ( 0 hom. 16 hem. )

Consequence

HDAC8
ENST00000412342.6 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.125

Publications

0 publications found

Variant links:

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: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Cornelia de Lange syndrome 5
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Wilson-Turner syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

HDAC8 links:

ENSG00000285547 (HGNC:):

ENSG00000285547 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000433 (47/1086614) while in subpopulation NFE AF = 0.0000541 (45/831761). AF 95% confidence interval is 0.0000412. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 47 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC8	NM_018486.3 link	c.-5G>A		5_prime_UTR_variant	Exon 1 of 11	ENST00000373573.9	NP_060956.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9 link	c.-5G>A		5_prime_UTR_variant	Exon 1 of 11	1	NM_018486.3	ENSP00000362674.3
ENSG00000285547	ENST00000648922.1 link	c.-5G>A		5_prime_UTR_variant	Exon 1 of 12			ENSP00000497072.1

Frequencies

GnomAD3 genomes

AF:

0.0000270

AC:

AN:

111014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000328

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000274

AC:

AN:

182725

AF XY:

0.0000595

show subpopulations

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:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000433

AC:

AN:

1086614

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

352334

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26203

American (AMR)

AF:

0.00

AC:

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19308

East Asian (EAS)

AF:

0.00

AC:

AN:

30167

South Asian (SAS)

AF:

0.00

AC:

AN:

53848

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40289

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4106

European-Non Finnish (NFE)

AF:

0.0000541

AC:

AN:

831761

Other (OTH)

AF:

0.0000437

AC:

AN:

45733

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000270

AC:

AN:

111014

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33170

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000328

AC:

AN:

30442

American (AMR)

AF:

0.00

AC:

AN:

10483

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3527

South Asian (SAS)

AF:

0.00

AC:

AN:

2562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5973

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52979

Other (OTH)

AF:

0.00

AC:

AN:

1480

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000302

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.13

PromoterAI

-0.26

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=300/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over