rs41312114

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006044.4(HDAC6):c.3248G>A(p.Gly1083Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,208,599 control chromosomes in the GnomAD database, including 6 homozygotes. There are 1,217 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1083S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., 57 hem., cov: 22)

Exomes 𝑓: 0.0034 ( 6 hom. 1160 hem. )

Consequence

HDAC6
NM_006044.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.33

Publications

7 publications found

Variant links:

Genes affected

HDAC6 (HGNC:14064): (histone deacetylase 6) 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 II of the histone deacetylase/acuc/apha family. It contains an internal duplication of two catalytic domains which appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription. [provided by RefSeq, Jul 2008]

HDAC6 Gene-Disease associations (from GenCC):

X-linked dominant chondrodysplasia, Chassaing-Lacombe type
Inheritance: XL Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

HDAC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010107607).

BP6

Variant X-48823730-G-A is Benign according to our data. Variant chrX-48823730-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 445469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC6	NM_006044.4 link	c.3248G>A	p.Gly1083Asp	missense_variant	Exon 26 of 29	ENST00000334136.11	NP_006035.2	Q9UBN7-1A0A024QZ26Q9NSW6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC6	ENST00000334136.11 link	c.3248G>A	p.Gly1083Asp	missense_variant	Exon 26 of 29	1	NM_006044.4	ENSP00000334061.5		Q9UBN7-1

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

222

AN:

111609

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000326

Gnomad AMI

AF:

0.00441

Gnomad AMR

AF:

0.000190

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:

0.00390

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00169

AC:

304

AN:

179820

AF XY:

0.00152

show subpopulations

Gnomad AFR exome

AF:

0.000620

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00112

GnomAD4 exome

AF:

0.00341

AC:

3744

AN:

1096941

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

1160

AN XY:

362359

show subpopulations

African (AFR)

AF:

0.000493

AC:

AN:

26384

American (AMR)

AF:

0.0000569

AC:

AN:

35139

Ashkenazi Jewish (ASJ)

AF:

0.000207

AC:

AN:

19361

East Asian (EAS)

AF:

0.00

AC:

AN:

30183

South Asian (SAS)

AF:

0.00

AC:

AN:

53900

European-Finnish (FIN)

AF:

0.000124

AC:

AN:

40455

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00433

AC:

3644

AN:

841340

Other (OTH)

AF:

0.00165

AC:

AN:

46044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

135

270

406

541

676

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

150

300

450

600

750

<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:

0.00199

AC:

222

AN:

111658

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

AN XY:

33822

show subpopulations

African (AFR)

AF:

0.000326

AC:

AN:

30721

American (AMR)

AF:

0.000190

AC:

AN:

10519

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00

AC:

AN:

2651

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6113

Middle Eastern (MID)

AF:

0.00

AC:

AN:

212

European-Non Finnish (NFE)

AF:

0.00390

AC:

207

AN:

53053

Other (OTH)

AF:

0.00

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00276

Hom.:

143

Bravo

AF:

0.00179

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00342

AC:

ExAC

AF:

0.00187

AC:

227

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 22, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HDAC6-related disorder

Benign:1

Mar 19, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

T;T;T;T;T;.

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

.;.;.;.;T;T

M_CAP

Pathogenic

0.66

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.1

M;M;M;M;M;.

PhyloP100

2.3

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.2

N;.;N;.;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.15

T;.;T;.;.;.

Sift4G

Uncertain

0.029

D;.;D;.;.;.

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.59

MVP

0.82

MPC

0.39

ClinPred

0.030

GERP RS

5.6

PromoterAI

0.030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.33

gMVP

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over