rs3791373

Variant names:

• chr2-239083142-A-G
• rs3791373
• NM_001378414.1:c.2533-921T>C

Variant summary

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

The NM_001378414.1(HDAC4):​c.2533-921T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,204 control chromosomes in the GnomAD database, including 11,463 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 0.38 (11463 hom., cov: 35)
• Consequence: HDAC4 NM_001378414.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.911
• Publications: 2 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), G2P, Ambry Genetics
• 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 (AMR) allele frequency at 95% confidence interval = 0.5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	NM_001378414.1	MANE Select	c.2533-921T>C		intron	N/A	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.2533-921T>C		intron	N/A	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.2518-921T>C		intron	N/A	NP_001365345.1	P56524-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC4	ENST00000543185.6	TSL:5 MANE Select	c.2533-921T>C		intron	N/A	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.2518-921T>C		intron	N/A	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000896768.1		c.2533-921T>C		intron	N/A	ENSP00000566827.1

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57962 AN: 152086 Hom.: 11447 Cov.: 35

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.402

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.378

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

GnomAD4 genome AF: 0.381 AC: 57996 AN: 152204 Hom.: 11463 Cov.: 35 AF XY: 0.384 AC XY: 28583 AN XY: 74404

African (AFR) AF: 0.307 AC: 12729 AN: 41524

American (AMR) AF: 0.509 AC: 7792 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.276 AC: 959 AN: 3470

East Asian (EAS) AF: 0.372 AC: 1923 AN: 5170

South Asian (SAS) AF: 0.377 AC: 1820 AN: 4824

European-Finnish (FIN) AF: 0.426 AC: 4517 AN: 10594

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26985 AN: 68000

Other (OTH) AF: 0.378 AC: 798 AN: 2110

Alfa AF: 0.390 Hom.: 22869

Bravo AF: 0.386

Asia WGS AF: 0.383 AC: 1328 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	0.56
DANN	Benign	0.26
PhyloP100		-0.91
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: rs3791373; hg19: chr2-240004838;