Variant X-48802739-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_006044.4(HDAC6):c.47G>A(p.Ser16Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,096,063 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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: not found (cov: 24)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

HDAC6
NM_006044.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.789

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 Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, HDAC6

BP4

Computational evidence support a benign effect (MetaRNN=0.08768296).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC6	NM_006044.4 linkuse as main transcript	c.47G>A	p.Ser16Asn	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.47G>A	p.Ser16Asn	missense_variant	2/29	1	NM_006044.4	P2	Q9UBN7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

176333

Hom.:

AF XY:

0.0000162

AC XY:

AN XY:

61605

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000223

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:

0.00000274

AC:

AN:

1096063

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

361617

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000997

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

Cov.:

ExAC

AF:

0.00000824

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

Feb 28, 2023

The c.47G>A (p.S16N) alteration is located in exon 2 (coding exon 1) of the HDAC6 gene. This alteration results from a G to A substitution at nucleotide position 47, causing the serine (S) at amino acid position 16 to be replaced by an asparagine (N). 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

Benign

0.098

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.96

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.66

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

M_CAP

Benign

0.013

MetaRNN

Benign

0.088

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

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.0

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

REVEL

Benign

0.078

Sift

Benign

0.11

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.0020, 0.017

.;.;.;.;B;B;B;B;B;.;B;B;B;.;.

Vest4

0.10, 0.083

MutPred

0.13

Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);Loss of phosphorylation at S16 (P = 0.0029);

MVP

0.60

MPC

1.0

ClinPred

0.033

GERP RS

2.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.22

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

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

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