X-48802743-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_006044.4(HDAC6):c.51G>C(p.Arg17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000389 in 1,207,114 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000020 ( 0 hom. 10 hem. )

Consequence

HDAC6
NM_006044.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0550

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=0.02738434).

BS2

High Hemizygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC6	NM_006044.4 linkuse as main transcript	c.51G>C	p.Arg17Ser	missense_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.51G>C	p.Arg17Ser	missense_variant	2/29	1	NM_006044.4	P2	Q9UBN7-1

Frequencies

GnomAD3 genomes

AF:

0.000225

AC:

AN:

111132

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

33320

show subpopulations

Gnomad AFR

AF:

0.000818

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:

0.0000568

AC:

AN:

176195

Hom.:

AF XY:

0.0000325

AC XY:

AN XY:

61507

show subpopulations

Gnomad AFR exome

AF:

0.000716

Gnomad AMR exome

AF:

0.0000371

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:

0.0000201

AC:

AN:

1095930

Hom.:

Cov.:

AF XY:

0.0000277

AC XY:

AN XY:

361488

show subpopulations

Gnomad4 AFR exome

AF:

0.000797

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:

0.0000217

GnomAD4 genome

AF:

0.000225

AC:

AN:

111184

Hom.:

Cov.:

AF XY:

0.000180

AC XY:

AN XY:

33382

show subpopulations

Gnomad4 AFR

AF:

0.000817

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:

0.000268

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 13, 2021

The c.51G>C (p.R17S) alteration is located in exon 2 (coding exon 1) of the HDAC6 gene. This alteration results from a G to C substitution at nucleotide position 51, causing the arginine (R) at amino acid position 17 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.42

Cadd

Benign

Dann

Benign

0.95

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.033

MetaRNN

Benign

0.027

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

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.1

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

REVEL

Benign

0.081

Sift

Uncertain

0.015

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.42, 0.94

.;.;.;.;B;P;B;B;P;.;B;B;P;.;.

Vest4

0.35, 0.29

MutPred

0.21

Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);Gain of phosphorylation at R17 (P = 6e-04);

MVP

0.62

MPC

1.0

ClinPred

0.022

GERP RS

-0.23

Varity_R

0.25

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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