dbSNP rs1239937279: HDAC8:c.1111+17G>A (chrX-72351716-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_018486.3(HDAC8):c.1111+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,161,708 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 4 hem. )

Consequence

HDAC8
NM_018486.3 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.88

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: 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

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant X-72351716-C-T is Benign according to our data. Variant chrX-72351716-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3706921.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000172 (18/1049303) while in subpopulation NFE AF = 0.0000213 (17/798666). AF 95% confidence interval is 0.000013. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 18 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HDAC8	NM_018486.3	MANE Select	c.1111+17G>A	intron	N/A	NP_060956.1	Q9BY41-1
HDAC8	NM_001410725.1		c.1111+17G>A	intron	N/A	NP_001397654.1	A0A3B3IS68
HDAC8	NM_001410727.1		c.1033+17G>A	intron	N/A	NP_001397656.1	A6NFW1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC8	ENST00000373573.9	TSL:1 MANE Select	c.1111+17G>A		intron	N/A	ENSP00000362674.3	Q9BY41-1
ENSG00000285547	ENST00000648922.1		c.1111+17G>A		intron	N/A	ENSP00000497072.1	A0A3B3IRV1
HDAC8	ENST00000373568.7	TSL:5	c.1128G>A	p.Ser376Ser	synonymous	Exon 10 of 10	ENSP00000362669.3	A6NGJ7

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112405

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000114

AC:

AN:

175336

AF XY:

0.00

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:

0.0000256

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000172

AC:

AN:

1049303

Hom.:

Cov.:

AF XY:

0.0000123

AC XY:

AN XY:

325465

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25439

American (AMR)

AF:

0.00

AC:

AN:

34914

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19030

East Asian (EAS)

AF:

0.00

AC:

AN:

29926

South Asian (SAS)

AF:

0.0000191

AC:

AN:

52451

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3985

European-Non Finnish (NFE)

AF:

0.0000213

AC:

AN:

798666

Other (OTH)

AF:

0.00

AC:

AN:

44500

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00000890

AC:

AN:

112405

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34559

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

30909

American (AMR)

AF:

0.00

AC:

AN:

10688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3564

South Asian (SAS)

AF:

0.00

AC:

AN:

2728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6144

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53274

Other (OTH)

AF:

0.00

AC:

AN:

1515

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cornelia de Lange syndrome 5 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.90

(source)

DANN

Benign

0.82

PhyloP100

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over