dbSNP rs73000144: HDAC4:p.Val320Ile (chr2-239139704-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001378414.1(HDAC4):c.958G>A(p.Val320Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,614,018 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0032 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 16 hom. )

Consequence

HDAC4
NM_001378414.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.56

Publications

8 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
2q37 microdeletion syndrome
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HDAC4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_001378414.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0073234737).

BP6

Variant 2-239139704-C-T is Benign according to our data. Variant chr2-239139704-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 284720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00319 (486/152354) while in subpopulation NFE AF = 0.00522 (355/68038). AF 95% confidence interval is 0.00477. There are 3 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 486 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	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC4	NM_001378414.1	MANE Select	c.958G>A	p.Val320Ile	missense	Exon 9 of 27	NP_001365343.1	A0A7I2SVS4
HDAC4	NM_001378415.1		c.958G>A	p.Val320Ile	missense	Exon 9 of 27	NP_001365344.1	A0A7I2SVS4
HDAC4	NM_001378416.1		c.958G>A	p.Val320Ile	missense	Exon 9 of 27	NP_001365345.1	P56524-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDAC4	ENST00000543185.6	TSL:5 MANE Select	c.958G>A	p.Val320Ile	missense	Exon 9 of 27	ENSP00000440481.3	A0A7I2SVS4
HDAC4	ENST00000345617.7	TSL:1	c.958G>A	p.Val320Ile	missense	Exon 9 of 27	ENSP00000264606.3	P56524-1
HDAC4	ENST00000461113.5	TSL:1	n.621G>A		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes

AF:

0.00319

AC:

485

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.00333

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.000376

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00520

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00304

AC:

761

AN:

250556

AF XY:

0.00326

show subpopulations

Gnomad AFR exome

AF:

0.000556

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00368

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000693

Gnomad NFE exome

AF:

0.00517

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00385

AC:

5633

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

2821

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.000687

AC:

AN:

33478

American (AMR)

AF:

0.00255

AC:

114

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00344

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.000626

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000675

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00458

AC:

5097

AN:

1111886

Other (OTH)

AF:

0.00349

AC:

211

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

305

610

914

1219

1524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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:

0.00319

AC:

486

AN:

152354

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

219

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41568

American (AMR)

AF:

0.00333

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000376

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00522

AC:

355

AN:

68038

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00400

Hom.:

Bravo

AF:

0.00336

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.80

M_CAP

Benign

0.023

MetaRNN

Benign

0.0073

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.25

PhyloP100

1.6

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.36

REVEL

Benign

0.028

Sift

Benign

0.47

Sift4G

Benign

0.25

Varity_R

0.037

gMVP

0.12

Mutation Taster

=297/3

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over