Genetic Variant HDAC9:c.415+99A>C (chr7-18590585-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_178425.4(HDAC9):c.415+99A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.657 in 1,183,904 control chromosomes in the GnomAD database, including 257,477 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.66 ( 32907 hom., cov: 31)

Exomes 𝑓: 0.66 ( 224570 hom. )

Consequence

HDAC9
NM_178425.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.259

Publications

9 publications found

Variant links:

Genes affected

HDAC9 (HGNC:14065): (histone deacetylase 9) 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 has sequence homology to members of the histone deacetylase family. This gene is orthologous to the Xenopus and mouse MITR genes. The MITR protein lacks the histone deacetylase catalytic domain. It represses MEF2 activity through recruitment of multicomponent corepressor complexes that include CtBP and HDACs. This encoded protein may play a role in hematopoiesis. Multiple alternatively spliced transcripts have been described for this gene but the full-length nature of some of them has not been determined. [provided by RefSeq, Jul 2008]

HDAC9 Gene-Disease associations (from GenCC):

auriculocondylar syndrome 4
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

HDAC9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC9	NM_178425.4 link	c.415+99A>C		intron_variant	Intron 4 of 25	ENST00000686413.1	NP_848512.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC9	ENST00000686413.1 link	c.415+99A>C		intron_variant	Intron 4 of 25		NM_178425.4	ENSP00000509161.1

Frequencies

GnomAD3 genomes

AF:

0.656

AC:

99581

AN:

151908

Hom.:

32855

Cov.:

show subpopulations

Gnomad AFR

AF:

0.628

Gnomad AMI

AF:

0.551

Gnomad AMR

AF:

0.687

Gnomad ASJ

AF:

0.707

Gnomad EAS

AF:

0.861

Gnomad SAS

AF:

0.775

Gnomad FIN

AF:

0.637

Gnomad MID

AF:

0.701

Gnomad NFE

AF:

0.642

Gnomad OTH

AF:

0.670

GnomAD4 exome

AF:

0.657

AC:

677885

AN:

1031878

Hom.:

224570

AF XY:

0.660

AC XY:

336436

AN XY:

509790

show subpopulations

African (AFR)

AF:

0.632

AC:

14452

AN:

22872

American (AMR)

AF:

0.691

AC:

14006

AN:

20266

Ashkenazi Jewish (ASJ)

AF:

0.718

AC:

12852

AN:

17910

East Asian (EAS)

AF:

0.884

AC:

29663

AN:

33572

South Asian (SAS)

AF:

0.765

AC:

40176

AN:

52524

European-Finnish (FIN)

AF:

0.629

AC:

28448

AN:

45220

Middle Eastern (MID)

AF:

0.700

AC:

2969

AN:

4244

European-Non Finnish (NFE)

AF:

0.639

AC:

505300

AN:

790304

Other (OTH)

AF:

0.668

AC:

30019

AN:

44966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

10966

21932

32898

43864

54830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12980

25960

38940

51920

64900

<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:

0.656

AC:

99694

AN:

152026

Hom.:

32907

Cov.:

AF XY:

0.659

AC XY:

48966

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.629

AC:

26054

AN:

41430

American (AMR)

AF:

0.687

AC:

10491

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.707

AC:

2452

AN:

3468

East Asian (EAS)

AF:

0.861

AC:

4459

AN:

5178

South Asian (SAS)

AF:

0.775

AC:

3737

AN:

4820

European-Finnish (FIN)

AF:

0.637

AC:

6734

AN:

10564

Middle Eastern (MID)

AF:

0.702

AC:

205

AN:

292

European-Non Finnish (NFE)

AF:

0.642

AC:

43635

AN:

67988

Other (OTH)

AF:

0.676

AC:

1426

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1724

3447

5171

6894

8618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

800

1600

2400

3200

4000

<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:

0.649

Hom.:

95353

Bravo

AF:

0.657

Asia WGS

AF:

0.835

AC:

2900

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.9

(source)

DANN

Benign

0.59

PhyloP100

0.26

Mutation Taster

=30/70

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over