Genetic Variant HDAC9:p.Ala140Ser (chr7-18591518-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178425.4(HDAC9):c.418G>T(p.Ala140Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HDAC9
NM_178425.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.89

Publications

8 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC9	NM_178425.4	MANE Select	c.418G>T	p.Ala140Ser	missense splice_region	Exon 5 of 26	NP_848512.1	Q9UKV0-7
HDAC9	NM_178423.3		c.409G>T	p.Ala137Ser	missense splice_region	Exon 5 of 26	NP_848510.1	Q9UKV0-5
HDAC9	NM_001321868.2		c.475G>T	p.Ala159Ser	missense splice_region	Exon 6 of 26	NP_001308797.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC9	ENST00000686413.1	MANE Select	c.418G>T	p.Ala140Ser	missense splice_region	Exon 5 of 26	ENSP00000509161.1	Q9UKV0-7
HDAC9	ENST00000441542.7	TSL:1	c.418G>T	p.Ala140Ser	missense splice_region	Exon 4 of 25	ENSP00000408617.2	Q9UKV0-7
HDAC9	ENST00000406451.8	TSL:1	c.409G>T	p.Ala137Ser	missense splice_region	Exon 5 of 26	ENSP00000384657.3	Q9UKV0-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

183152

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1419726

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702150

African (AFR)

AF:

0.00

AC:

AN:

32260

American (AMR)

AF:

0.00

AC:

AN:

37530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25332

East Asian (EAS)

AF:

0.00

AC:

AN:

37568

South Asian (SAS)

AF:

0.00

AC:

AN:

81024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090904

Other (OTH)

AF:

0.00

AC:

AN:

58938

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000838

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.079

MetaRNN

Uncertain

0.57

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.1

PhyloP100

9.9

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.52

Sift

Uncertain

0.0020

Sift4G

Benign

0.18

Polyphen

0.91

Vest4

0.69

MutPred

0.32

Gain of phosphorylation at A137 (P = 0.0039)

MVP

0.89

MPC

0.54

ClinPred

0.94

GERP RS

5.7

Varity_R

0.24

gMVP

0.42

Mutation Taster

=41/59

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over