NM_001378414.1:c.3235G>A

Variant names:

• chr2-239053132-C-T
• NM_001378414.1:c.3235G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378414.1(HDAC4):​c.3235G>A​(p.Asp1079Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HDAC4 NM_001378414.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.51
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16315106).

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.3235G>A	p.Asp1079Asn	missense	Exon 27 of 27	NP_001365343.1	A0A7I2SVS4
	HDAC4	NM_001378415.1		c.3235G>A	p.Asp1079Asn	missense	Exon 27 of 27	NP_001365344.1	A0A7I2SVS4
	HDAC4	NM_001378416.1		c.3220G>A	p.Asp1074Asn	missense	Exon 27 of 27	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.3235G>A	p.Asp1079Asn	missense	Exon 27 of 27	ENSP00000440481.3	A0A7I2SVS4
	HDAC4	ENST00000345617.7	TSL:1	c.3220G>A	p.Asp1074Asn	missense	Exon 27 of 27	ENSP00000264606.3	P56524-1
	HDAC4	ENST00000896768.1		c.3235G>A	p.Asp1079Asn	missense	Exon 27 of 27	ENSP00000566827.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461862 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.12
Sift	Uncertain	0.029	D
Sift4G	Benign	0.32	T
Polyphen		0.010	B
Vest4		0.20
MutPred		0.068		Gain of glycosylation at P1073 (P = 0.1376)
MVP		0.61
MPC		0.25
ClinPred		0.60	D
GERP RS		4.6
Varity_R		0.088
gMVP		0.10
Mutation Taster		=89/11	polymorphism

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

hg19: chr2-239974828;