Genetic Variant HDAC6:c.223-10T>C (chrX-48803118-T-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006044.4(HDAC6):c.223-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,204,093 control chromosomes in the GnomAD database, including 5 homozygotes. There are 162 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., 15 hem., cov: 23)

Exomes 𝑓: 0.00035 ( 5 hom. 147 hem. )

Consequence

HDAC6
NM_006044.4 intron

Scores

Splicing: ADA: 0.00002121

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0470

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

HDAC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant X-48803118-T-C is Benign according to our data. Variant chrX-48803118-T-C is described in ClinVar as Benign. ClinVar VariationId is 712880.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 15 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006044.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HDAC6	NM_006044.4	MANE Select	c.223-10T>C	intron	N/A	NP_006035.2
HDAC6	NM_001321225.2		c.265-10T>C	intron	N/A	NP_001308154.1	B4DZH6
HDAC6	NM_001321226.2		c.223-10T>C	intron	N/A	NP_001308155.1	Q9UBN7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HDAC6	ENST00000334136.11	TSL:1 MANE Select	c.223-10T>C	intron	N/A	ENSP00000334061.5	Q9UBN7-1
HDAC6	ENST00000376619.7	TSL:1	c.223-10T>C	intron	N/A	ENSP00000365804.2	Q9UBN7-1
HDAC6	ENST00000462730.5	TSL:1	c.223-10T>C	intron	N/A	ENSP00000496727.1	Q9BRX7

Frequencies

GnomAD3 genomes

AF:

0.000686

AC:

AN:

110710

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000192

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000848

Gnomad SAS

AF:

0.00152

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000542

AC:

AN:

178940

AF XY:

0.000580

show subpopulations

Gnomad AFR exome

AF:

0.00233

Gnomad AMR exome

AF:

0.000333

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.000225

GnomAD4 exome

AF:

0.000347

AC:

379

AN:

1093336

Hom.:

Cov.:

AF XY:

0.000409

AC XY:

147

AN XY:

359038

show subpopulations

African (AFR)

AF:

0.00300

AC:

AN:

26290

American (AMR)

AF:

0.000286

AC:

AN:

34980

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19329

East Asian (EAS)

AF:

0.00288

AC:

AN:

30181

South Asian (SAS)

AF:

0.00188

AC:

101

AN:

53593

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40450

Middle Eastern (MID)

AF:

0.000243

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

838482

Other (OTH)

AF:

0.00185

AC:

AN:

45912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000713

AC:

AN:

110757

Hom.:

Cov.:

AF XY:

0.000454

AC XY:

AN XY:

33029

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

30443

American (AMR)

AF:

0.000192

AC:

AN:

10433

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.000851

AC:

AN:

3524

South Asian (SAS)

AF:

0.00152

AC:

AN:

2626

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5866

Middle Eastern (MID)

AF:

0.00

AC:

AN:

213

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52830

Other (OTH)

AF:

0.00

AC:

AN:

1501

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000712

Hom.:

Bravo

AF:

0.000801

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

6.9

(source)

DANN

Benign

0.69

PhyloP100

0.047

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.0020

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over