2-239084137-C-T

Variant names:

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.2532+18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,599,570 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

HDAC4
NM_001378414.1 intron

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0290

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), Ambry Genetics, G2P
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 2-239084137-C-T is Benign according to our data. Variant chr2-239084137-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 445663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00164 (250/152326) while in subpopulation AFR AF = 0.0057 (237/41562). AF 95% confidence interval is 0.00511. There are 2 homozygotes in GnomAd4. There are 113 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 250 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC4	NM_001378414.1 link	c.2532+18G>A		intron_variant	Intron 20 of 26	ENST00000543185.6	NP_001365343.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HDAC4	ENST00000543185.6 link	c.2532+18G>A	intron_variant	Intron 20 of 26	5	NM_001378414.1	ENSP00000440481.3	A0A7I2SVS4
HDAC4	ENST00000345617.7 link	c.2517+18G>A	intron_variant	Intron 20 of 26	1		ENSP00000264606.3	P56524-1
HDAC4	ENST00000487617.5 link	n.424+18G>A	intron_variant	Intron 6 of 7	3
HDAC4	ENST00000690129.1 link	n.546+18G>A	intron_variant	Intron 3 of 9

Frequencies

GnomAD3 genomes

AF:

0.00164

AC:

249

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00569

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000415

AC:

101

AN:

243272

AF XY:

0.000349

show subpopulations

Gnomad AFR exome

AF:

0.00593

Gnomad AMR exome

AF:

0.000235

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:

0.000335

GnomAD4 exome

AF:

0.000144

AC:

209

AN:

1447244

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

720382

show subpopulations

African (AFR)

AF:

0.00547

AC:

181

AN:

33076

American (AMR)

AF:

0.000226

AC:

AN:

44316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25998

East Asian (EAS)

AF:

0.00

AC:

AN:

39402

South Asian (SAS)

AF:

0.00

AC:

AN:

85258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100470

Other (OTH)

AF:

0.000284

AC:

AN:

59950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00164

AC:

250

AN:

152326

Hom.:

Cov.:

AF XY:

0.00152

AC XY:

113

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00570

AC:

237

AN:

41562

American (AMR)

AF:

0.000653

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

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:

0.000897

Hom.:

Bravo

AF:

0.00174

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Chromosome 2q37 deletion syndrome;C5676944:Neurodevelopmental disorder with central hypotonia and dysmorphic facies

Benign:1

Nov 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.29

(source)

DANN

Benign

0.61

PhyloP100

0.029

RBP_binding_hub_radar

0.67

RBP_regulation_power_radar

1.8

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over