2-239053498-C-T

Position:

• chr2-239053498-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001378414.1(HDAC4):​c.3192G>A​(p.Met1064Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HDAC4 NM_001378414.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.98

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HDAC4. . Gene score misZ 2.926 (greater than the threshold 3.09). Trascript score misZ 3.7504 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with central hypotonia and dysmorphic facies, 2q37 microdeletion syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3151719).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC4	NM_001378414.1	c.3192G>A	p.Met1064Ile	missense_variant	26/27	ENST00000543185.6	NP_001365343.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC4	ENST00000543185.6	c.3192G>A	p.Met1064Ile	missense_variant	26/27	5	NM_001378414.1	ENSP00000440481	A1
HDAC4	ENST00000345617.7	c.3177G>A	p.Met1059Ile	missense_variant	26/27	1		ENSP00000264606	P4
HDAC4	ENST00000430200.1	c.450G>A	p.Met150Ile	missense_variant	3/4	3		ENSP00000410551
HDAC4	ENST00000690129.1	n.1206G>A		non_coding_transcript_exon_variant	9/10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2024

The c.3177G>A (p.M1059I) alteration is located in exon 26 (coding exon 25) of the HDAC4 gene. This alteration results from a G to A substitution at nucleotide position 3177, causing the methionine (M) at amino acid position 1059 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.086
Sift	Uncertain	0.016	D;.
Sift4G	Benign	0.12	T;T
Polyphen		0.0	B;.
Vest4		0.56
MutPred		0.33		Gain of sheet (P = 0.0344);.;
MVP		0.50
MPC		0.29
ClinPred		0.86	D
GERP RS		3.7
Varity_R		0.37
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-239975194;