NM_018486.3:c.20C>T

Variant names:

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

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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