Genetic Variant HDAC9:p.Phe1010Phe (chr7-18954247-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The ENST00000432645.6(HDAC9):c.3030C>T(p.Phe1010Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,368,696 control chromosomes in the GnomAD database, including 395,978 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.77 ( 45700 hom., cov: 32)

Exomes 𝑓: 0.76 ( 350278 hom. )

Consequence

HDAC9
ENST00000432645.6 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.337

Publications

17 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 7-18954247-C-T is Benign according to our data. Variant chr7-18954247-C-T is described in ClinVar as Benign. ClinVar VariationId is 402925.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.337 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000432645.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HDAC9	NM_178425.4	MANE Select	c.3022+17C>T		intron	N/A	NP_848512.1
HDAC9	NM_058176.2		c.3030C>T	p.Phe1010Phe	synonymous	Exon 23 of 23	NP_478056.1
HDAC9	NM_178423.3		c.3013+17C>T		intron	N/A	NP_848510.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HDAC9	ENST00000432645.6	TSL:1	c.3030C>T	p.Phe1010Phe	synonymous	Exon 23 of 23	ENSP00000410337.2
HDAC9	ENST00000686413.1	MANE Select	c.3022+17C>T		intron	N/A	ENSP00000509161.1
HDAC9	ENST00000441542.7	TSL:1	c.3022+17C>T		intron	N/A	ENSP00000408617.2

Frequencies

GnomAD3 genomes

AF:

0.775

AC:

117682

AN:

151872

Hom.:

45654

Cov.:

show subpopulations

Gnomad AFR

AF:

0.809

Gnomad AMI

AF:

0.702

Gnomad AMR

AF:

0.809

Gnomad ASJ

AF:

0.767

Gnomad EAS

AF:

0.715

Gnomad SAS

AF:

0.780

Gnomad FIN

AF:

0.765

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.754

Gnomad OTH

AF:

0.762

GnomAD2 exomes

AF:

0.776

AC:

122720

AN:

158116

AF XY:

0.774

show subpopulations

Gnomad AFR exome

AF:

0.805

Gnomad AMR exome

AF:

0.872

Gnomad ASJ exome

AF:

0.772

Gnomad EAS exome

AF:

0.713

Gnomad FIN exome

AF:

0.761

Gnomad NFE exome

AF:

0.752

Gnomad OTH exome

AF:

0.758

GnomAD4 exome

AF:

0.758

AC:

921878

AN:

1216708

Hom.:

350278

Cov.:

AF XY:

0.759

AC XY:

461809

AN XY:

608528

show subpopulations

African (AFR)

AF:

0.802

AC:

22187

AN:

27674

American (AMR)

AF:

0.862

AC:

29881

AN:

34662

Ashkenazi Jewish (ASJ)

AF:

0.779

AC:

18614

AN:

23894

East Asian (EAS)

AF:

0.704

AC:

24839

AN:

35302

South Asian (SAS)

AF:

0.782

AC:

57631

AN:

73702

European-Finnish (FIN)

AF:

0.759

AC:

37582

AN:

49508

Middle Eastern (MID)

AF:

0.736

AC:

3709

AN:

5038

European-Non Finnish (NFE)

AF:

0.752

AC:

687972

AN:

915012

Other (OTH)

AF:

0.760

AC:

39463

AN:

51916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

10545

21091

31636

42182

52727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15806

31612

47418

63224

79030

<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:

0.775

AC:

117786

AN:

151988

Hom.:

45700

Cov.:

AF XY:

0.778

AC XY:

57762

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.809

AC:

33565

AN:

41494

American (AMR)

AF:

0.809

AC:

12323

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.767

AC:

2660

AN:

3470

East Asian (EAS)

AF:

0.715

AC:

3685

AN:

5154

South Asian (SAS)

AF:

0.779

AC:

3756

AN:

4822

European-Finnish (FIN)

AF:

0.765

AC:

8084

AN:

10562

Middle Eastern (MID)

AF:

0.759

AC:

223

AN:

294

European-Non Finnish (NFE)

AF:

0.754

AC:

51239

AN:

67946

Other (OTH)

AF:

0.765

AC:

1612

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1369

2738

4108

5477

6846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

870

1740

2610

3480

4350

<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:

0.764

Hom.:

28343

Bravo

AF:

0.778

Asia WGS

AF:

0.761

AC:

2636

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.4

(source)

DANN

Benign

0.63

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over