chr5-141625208-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003883.4(HDAC3):c.1217G>A(p.Arg406Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,449,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HDAC3
NM_003883.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.18

Publications

0 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:

ENSG00000228737 (HGNC:):

ENSG00000228737 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.1217G>A	p.Arg406Lys	missense splice_region	Exon 14 of 15	NP_003874.2
HDAC3	NM_001355039.2		c.1217G>A	p.Arg406Lys	missense	Exon 14 of 14	NP_001341968.1
HDAC3	NM_001355040.2		c.758G>A	p.Arg253Lys	missense splice_region	Exon 12 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.1217G>A	p.Arg406Lys	missense splice_region	Exon 14 of 15	ENSP00000302967.3	O15379-1
HDAC3	ENST00000469550.6	TSL:1	n.1290G>A		splice_region non_coding_transcript_exon	Exon 12 of 13
HDAC3	ENST00000937593.1		c.1241G>A	p.Arg414Lys	missense splice_region	Exon 14 of 15	ENSP00000607652.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449322

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720714

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32790

American (AMR)

AF:

0.00

AC:

AN:

40644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25642

East Asian (EAS)

AF:

0.00

AC:

AN:

39486

South Asian (SAS)

AF:

0.00

AC:

AN:

83746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5260

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108550

Other (OTH)

AF:

0.00

AC:

AN:

59834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.11

Eigen

Benign

0.072

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.034

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-0.14

PhyloP100

7.2

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

0.41

REVEL

Benign

0.15

Sift

Benign

0.82

Sift4G

Benign

0.41

Polyphen

0.18

Vest4

0.52

MutPred

0.32

Gain of ubiquitination at R406 (P = 0.0025)

MVP

0.57

MPC

1.2

ClinPred

0.85

GERP RS

5.3

Varity_R

0.23

gMVP

0.63

Mutation Taster

=23/77

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.78

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.78

Position offset: 0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over