rs147689487

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_018486.3(HDAC8):c.20C>T(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,207,060 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P7R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000091 ( 0 hom., 1 hem., cov: 21)

Exomes 𝑓: 0.0000082 ( 0 hom. 4 hem. )

Consequence

HDAC8
NM_018486.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.72

Publications

1 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 (MetaRNN=0.07886726).

BP6

Variant X-72572742-G-A is Benign according to our data. Variant chrX-72572742-G-A is described in ClinVar as Benign. ClinVar VariationId is 599425.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000821 (9/1096802) while in subpopulation SAS AF = 0.0000739 (4/54108). AF 95% confidence interval is 0.0000252. There are 0 homozygotes in GnomAdExome4. There are 4 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 9 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC8	NM_018486.3 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 11	ENST00000373573.9	NP_060956.1	Q9BY41-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC8	ENST00000373573.9 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 11	1	NM_018486.3	ENSP00000362674.3		Q9BY41-1
ENSG00000285547	ENST00000648922.1 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 12			ENSP00000497072.1		A0A3B3IRV1

Frequencies

GnomAD3 genomes

AF:

0.00000907

AC:

AN:

110258

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:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183153

AF XY:

0.0000296

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1096802

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

362184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26374

American (AMR)

AF:

0.00

AC:

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19373

East Asian (EAS)

AF:

0.00

AC:

AN:

30193

South Asian (SAS)

AF:

0.0000739

AC:

AN:

54108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40435

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.00000476

AC:

AN:

840948

Other (OTH)

AF:

0.0000217

AC:

AN:

46039

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

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:

0.00000907

AC:

AN:

110258

Hom.:

Cov.:

AF XY:

0.0000308

AC XY:

AN XY:

32496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30177

American (AMR)

AF:

0.00

AC:

AN:

10387

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3504

South Asian (SAS)

AF:

0.00

AC:

AN:

2493

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5847

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52811

Other (OTH)

AF:

0.00

AC:

AN:

1475

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 14, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BS2, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and is predicted to be tolerated by multiple functional prediction tools. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

.;T;T;.;.;.;.;.;.;.;.;T;.;T;.;.;.;.;.;.;.;.;T;.;.;.;.

FATHMM_MKL

Benign

0.12

LIST_S2

Pathogenic

0.97

D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.037

MetaRNN

Benign

0.079

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

.;.;N;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;N;N

PhyloP100

1.7

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.8

.;D;N;.;.;.;N;.;.;.;.;N;.;N;.;.;.;N;.;N;.;.;N;N;.;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0050

.;D;D;.;.;.;D;.;.;.;.;D;.;D;.;.;.;D;.;D;.;.;D;D;.;D;D

Sift4G

Uncertain

0.018

.;D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;D;.;D;D

Polyphen

0.0

.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.13, 0.086, 0.098, 0.063, 0.087, 0.17, 0.14, 0.12, 0.12

MutPred

0.36

Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);Loss of disorder (P = 0.037);

MVP

0.60

MPC

1.0

ClinPred

0.11

GERP RS

2.9

PromoterAI

0.0039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.084

gMVP

0.53

Mutation Taster

=291/9

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

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over