X-48823531-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_006044.4(HDAC6):c.3132A>G(p.Ile1044Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,208,169 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 237 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.00064 ( 0 hom. 230 hem. )

Consequence

HDAC6
NM_006044.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.0900

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03717178).

BP6

Variant X-48823531-A-G is Benign according to our data. Variant chrX-48823531-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445380.

BS2

High Hemizygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC6	NM_006044.4 link	c.3132A>G	p.Ile1044Met	missense_variant	Exon 25 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.3132A>G	p.Ile1044Met	missense_variant	Exon 25 of 29	1	NM_006044.4	ENSP00000334061.5		Q9UBN7-1

Frequencies

GnomAD3 genomes

AF:

0.000261

AC:

AN:

111313

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000980

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000381

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:

0.000416

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000297

AC:

AN:

178710

AF XY:

0.000219

show subpopulations

Gnomad AFR exome

AF:

0.000237

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000593

Gnomad OTH exome

AF:

0.000452

GnomAD4 exome

AF:

0.000639

AC:

701

AN:

1096856

Hom.:

Cov.:

AF XY:

0.000635

AC XY:

230

AN XY:

362284

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26377

American (AMR)

AF:

0.000114

AC:

AN:

35148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19336

East Asian (EAS)

AF:

0.00

AC:

AN:

30169

South Asian (SAS)

AF:

0.00

AC:

AN:

53863

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40374

Middle Eastern (MID)

AF:

0.00145

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.000782

AC:

658

AN:

841414

Other (OTH)

AF:

0.000695

AC:

AN:

46040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<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:

0.000261

AC:

AN:

111313

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

AN XY:

33499

show subpopulations

African (AFR)

AF:

0.0000980

AC:

AN:

30606

American (AMR)

AF:

0.000381

AC:

AN:

10486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2615

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000416

AC:

AN:

52929

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

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:

0.000391

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000264

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 07, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 25, 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

- -

not specified

Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3132A>G (p.I1044M) alteration is located in exon 25 (coding exon 24) of the HDAC6 gene. This alteration results from a A to G substitution at nucleotide position 3132, causing the isoleucine (I) at amino acid position 1044 to be replaced by a methionine (M). 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

0.076

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.66

CADD

Benign

4.4

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

T;T;T;T;T;.

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.73

.;.;.;.;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.037

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L;L;L;.

PhyloP100

0.090

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.42

N;.;N;.;.;.

REVEL

Benign

0.033

Sift

Uncertain

0.020

D;.;D;.;.;.

Sift4G

Benign

0.14

T;.;T;.;.;.

Polyphen

0.40

B;B;B;B;B;.

Vest4

0.12

MVP

0.54

MPC

0.088

ClinPred

0.0050

GERP RS

2.8

PromoterAI

0.0064

Neutral

(source)

Varity_R

0.12

gMVP

0.10

Mutation Taster

=100/0

polymorphism

(source)

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

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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