Variant chrX-48823730-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 445469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48823730-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 57 XL gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.00199

AC:

222

AN:

111609

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

AN XY:

33763

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

GnomAD3 exomes

AF:

0.00169

AC:

304

AN:

179820

Hom.:

AF XY:

0.00152

AC XY:

AN XY:

64574

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 SAS 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

Gnomad4 AFR exome

AF:

0.000493

Gnomad4 AMR exome

AF:

0.0000569

Gnomad4 ASJ exome

AF:

0.000207

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000124

Gnomad4 NFE exome

AF:

0.00433

Gnomad4 OTH exome

AF:

0.00165

GnomAD4 genome

AF:

0.00199

AC:

222

AN:

111658

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

AN XY:

33822

show subpopulations

Gnomad4 AFR

AF:

0.000326

Gnomad4 AMR

AF:

0.000190

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00390

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00298

Hom.:

118

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 22, 2017	- -

HDAC6-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2020

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

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;.

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.33

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over