chr2-239339635-T-A

Variant names:

• chr2-239339635-T-A
• rs10177619
• NM_001378414.1:c.22+13043A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001378414.1(HDAC4):​c.22+13043A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.539 in 152,066 control chromosomes in the GnomAD database, including 22,397 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (22397 hom., cov: 32)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.407
• Publications: 7 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	NM_001378414.1	MANE Select	c.22+13043A>T		intron	N/A	NP_001365343.1
	HDAC4	NM_001378415.1		c.22+13043A>T		intron	N/A	NP_001365344.1
	HDAC4	NM_001378416.1		c.22+13043A>T		intron	N/A	NP_001365345.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	ENST00000543185.6	TSL:5 MANE Select	c.22+13043A>T		intron	N/A	ENSP00000440481.3
	HDAC4	ENST00000345617.7	TSL:1	c.22+13043A>T		intron	N/A	ENSP00000264606.3
	HDAC4	ENST00000493582.5	TSL:1	n.494+13043A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81898 AN: 151948 Hom.: 22347 Cov.: 32

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.491

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.588

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.499

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.523

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.539 AC: 82006 AN: 152066 Hom.: 22397 Cov.: 32 AF XY: 0.538 AC XY: 40003 AN XY: 74338

African (AFR) AF: 0.606 AC: 25132 AN: 41460

American (AMR) AF: 0.505 AC: 7719 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1751 AN: 3468

East Asian (EAS) AF: 0.588 AC: 3039 AN: 5172

South Asian (SAS) AF: 0.541 AC: 2614 AN: 4828

European-Finnish (FIN) AF: 0.499 AC: 5276 AN: 10578

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.512 AC: 34779 AN: 67974

Other (OTH) AF: 0.527 AC: 1113 AN: 2110

Alfa AF: 0.522 Hom.: 2574

Bravo AF: 0.541

Asia WGS AF: 0.614 AC: 2133 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.42
DANN	Benign	0.55
PhyloP100		-0.41
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10177619; hg19: chr2-240261330;