Variant X-48802784-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_ModerateBP6_ModerateBS2

The NM_006044.4(HDAC6):c.92C>G(p.Ser31Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,204,965 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. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000081 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.0000073 ( 0 hom. 3 hem. )

Consequence

HDAC6
NM_006044.4 missense, splice_region

Scores

Splicing: ADA: 0.009792

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.323

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 -7 ACMG points.

PP2

Missense variant where missense usually causes diseases, HDAC6

BP4

Computational evidence support a benign effect (MetaRNN=0.09366143).

BP6

Variant X-48802784-C-G is Benign according to our data. Variant chrX-48802784-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2660468.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC6	NM_006044.4 linkuse as main transcript	c.92C>G	p.Ser31Trp	missense_variant, splice_region_variant	2/29	ENST00000334136.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC6	ENST00000334136.11 linkuse as main transcript	c.92C>G	p.Ser31Trp	missense_variant, splice_region_variant	2/29	1	NM_006044.4	P2	Q9UBN7-1

Frequencies

GnomAD3 genomes

AF:

0.0000806

AC:

AN:

111676

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

33842

show subpopulations

Gnomad AFR

AF:

0.000293

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000235

AC:

AN:

169871

Hom.:

AF XY:

0.0000178

AC XY:

AN XY:

56321

show subpopulations

Gnomad AFR exome

AF:

0.000329

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000732

AC:

AN:

1093289

Hom.:

Cov.:

AF XY:

0.00000835

AC XY:

AN XY:

359251

show subpopulations

Gnomad4 AFR exome

AF:

0.000304

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000806

AC:

AN:

111676

Hom.:

Cov.:

AF XY:

0.0000591

AC XY:

AN XY:

33842

show subpopulations

Gnomad4 AFR

AF:

0.000293

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000106

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

HDAC6: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.94

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.79

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

M_CAP

Benign

0.019

MetaRNN

Benign

0.094

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

MetaSVM

Benign

-0.87

MutationTaster

Benign

0.56

D;D;N;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.6

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

REVEL

Benign

0.16

Sift

Benign

0.19

T;T;D;D;T;.;T;T;.;.;.;.;T;T;T

Sift4G

Uncertain

0.017

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

Polyphen

0.98, 1.0

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

Vest4

0.20, 0.18

MutPred

0.28

Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);Loss of phosphorylation at S31 (P = 0.023);

MVP

0.66

MPC

1.8

ClinPred

0.19

GERP RS

1.5

Varity_R

0.082

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0098

dbscSNV1_RF

Benign

0.12

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.22

Position offset: -46

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