Genetic Variant HDAC4:c.3230+18C>T (chr2-239053442-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001378414.1(HDAC4):c.3230+18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,610,110 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 5 hom. )

Consequence

HDAC4
NM_001378414.1 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.178

Publications

0 publications found

Variant links:

Genes affected

HDAC4 (HGNC:14063): (histone deacetylase 4) 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 class II of the histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. This protein does not bind DNA directly, but through transcription factors MEF2C and MEF2D. It seems to interact in a multiprotein complex with RbAp48 and HDAC3. [provided by RefSeq, Jul 2008]

HDAC4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with central hypotonia and dysmorphic facies
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
2q37 microdeletion syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HDAC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 2-239053442-G-A is Benign according to our data. Variant chr2-239053442-G-A is described in ClinVar as Benign. ClinVar VariationId is 2887533.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00109 (166/152326) while in subpopulation NFE AF = 0.00193 (131/68024). AF 95% confidence interval is 0.00166. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 166 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378414.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HDAC4	NM_001378414.1	MANE Select	c.3230+18C>T	intron	N/A	NP_001365343.1	A0A7I2SVS4
HDAC4	NM_001378415.1		c.3230+18C>T	intron	N/A	NP_001365344.1	A0A7I2SVS4
HDAC4	NM_001378416.1		c.3215+18C>T	intron	N/A	NP_001365345.1	P56524-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HDAC4	ENST00000543185.6	TSL:5 MANE Select	c.3230+18C>T	intron	N/A	ENSP00000440481.3	A0A7I2SVS4
HDAC4	ENST00000345617.7	TSL:1	c.3215+18C>T	intron	N/A	ENSP00000264606.3	P56524-1
HDAC4	ENST00000896768.1		c.3230+18C>T	intron	N/A	ENSP00000566827.1

Frequencies

GnomAD3 genomes

AF:

0.00109

AC:

166

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000579

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00193

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00110

AC:

272

AN:

248274

AF XY:

0.000974

show subpopulations

Gnomad AFR exome

AF:

0.000872

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.000807

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000749

Gnomad NFE exome

AF:

0.00195

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.00172

AC:

2503

AN:

1457784

Hom.:

Cov.:

AF XY:

0.00161

AC XY:

1168

AN XY:

724678

show subpopulations

African (AFR)

AF:

0.000718

AC:

AN:

33424

American (AMR)

AF:

0.000292

AC:

AN:

44566

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

25988

East Asian (EAS)

AF:

0.0000505

AC:

AN:

39606

South Asian (SAS)

AF:

0.0000349

AC:

AN:

85996

European-Finnish (FIN)

AF:

0.000761

AC:

AN:

52568

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00209

AC:

2318

AN:

1109740

Other (OTH)

AF:

0.00118

AC:

AN:

60248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

136

272

409

545

681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.00109

AC:

166

AN:

152326

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000577

AC:

AN:

41574

American (AMR)

AF:

0.000327

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00193

AC:

131

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00133

Hom.:

Bravo

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Benign

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.29

(source)

DANN

Benign

0.59

PhyloP100

-0.18

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over