Genetic Variant HDAC3:p.Gly99Arg (chr5-141630112-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003883.4(HDAC3):c.295G>C(p.Gly99Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HDAC3
NM_003883.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.72

Publications

4 publications found

Variant links:

Genes affected

HDAC3 (HGNC:4854): (histone deacetylase 3) 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 the histone deacetylase/acuc/apha family. It has histone deacetylase activity and represses transcription when tethered to a promoter. It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumor suppressor gene. [provided by RefSeq, Jul 2008]

HDAC3 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P

HDAC3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003883.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HDAC3	NM_003883.4	MANE Select	c.295G>C	p.Gly99Arg	missense	Exon 4 of 15	NP_003874.2
HDAC3	NM_001355039.2		c.295G>C	p.Gly99Arg	missense	Exon 4 of 14	NP_001341968.1
HDAC3	NM_001355040.2		c.-109G>C		5_prime_UTR	Exon 3 of 13	NP_001341969.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC3	ENST00000305264.8	TSL:1 MANE Select	c.295G>C	p.Gly99Arg	missense	Exon 4 of 15	ENSP00000302967.3	O15379-1
HDAC3	ENST00000469550.6	TSL:1	n.368G>C		non_coding_transcript_exon	Exon 2 of 13
HDAC3	ENST00000937593.1		c.295G>C	p.Gly99Arg	missense	Exon 4 of 15	ENSP00000607652.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251472

AF XY:

0.00000736

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

2.9

PhyloP100

7.7

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.026

Polyphen

1.0

Vest4

0.95

MutPred

0.75

Gain of solvent accessibility (P = 0.0971)

MVP

0.90

MPC

2.6

ClinPred

1.0

GERP RS

5.3

Varity_R

0.94

gMVP

0.91

Mutation Taster

=36/64

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over