chr2-239191276-G-A

Variant names:

• chr2-239191276-G-A
• rs3791556
• NM_001378414.1:c.95-1199C>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.95-1199C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 152,224 control chromosomes in the GnomAD database, including 2,284 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 0.17 (2284 hom., cov: 33)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 14 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=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.262 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC4	NM_001378414.1	c.95-1199C>T		intron_variant	Intron 3 of 26	ENST00000543185.6	NP_001365343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC4	ENST00000543185.6	c.95-1199C>T		intron_variant	Intron 3 of 26	5	NM_001378414.1	ENSP00000440481.3

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25156 AN: 152106 Hom.: 2282 Cov.: 33

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.168

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

GnomAD4 genome AF: 0.165 AC: 25152 AN: 152224 Hom.: 2284 Cov.: 33 AF XY: 0.169 AC XY: 12602 AN XY: 74434

African (AFR) AF: 0.135 AC: 5628 AN: 41538

American (AMR) AF: 0.256 AC: 3918 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 415 AN: 3470

East Asian (EAS) AF: 0.274 AC: 1417 AN: 5172

South Asian (SAS) AF: 0.194 AC: 938 AN: 4824

European-Finnish (FIN) AF: 0.150 AC: 1592 AN: 10606

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10806 AN: 68002

Other (OTH) AF: 0.165 AC: 348 AN: 2108

Alfa AF: 0.164 Hom.: 6654

Bravo AF: 0.171

Asia WGS AF: 0.216 AC: 754 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.7
DANN	Benign	0.81
PhyloP100		-0.14
PromoterAI		-0.0024	Neutral
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: rs3791556; hg19: chr2-240112972;