2-239053523-TCGTTCTCGCAAGTCTGAGCCTCGATCAGAGAA-T

Position:

• chr2-239053523-TCGTTCTCGCAAGTCTGAGCCTCGATCAGAGAA-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001378414.1(HDAC4):​c.3135_3166del​(p.Ser1046ArgfsTer24) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HDAC4 NM_001378414.1 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.73

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 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0413 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC4	NM_001378414.1	c.3135_3166del	p.Ser1046ArgfsTer24	frameshift_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.3135_3166del	p.Ser1046ArgfsTer24	frameshift_variant	26/27	5	NM_001378414.1	ENSP00000440481	A1
HDAC4	ENST00000345617.7	c.3120_3151del	p.Ser1041ArgfsTer24	frameshift_variant	26/27	1		ENSP00000264606	P4
HDAC4	ENST00000430200.1	c.392_423del	p.Ser132ArgfsTer24	frameshift_variant	3/4	3		ENSP00000410551
HDAC4	ENST00000690129.1	n.1149_1180del		non_coding_transcript_exon_variant	9/10

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 15, 2018

A variant of uncertain significance has been identified in the HDAC4 gene. The c.3120_3151del32 variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3120_3151del32 variant is not observed in large population cohorts (Lek et al., 2016). The c.3120_3151del32 variant causes a frameshift starting with codon Serine 1041, changes this amino acid to a Arginine residue and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Ser1041ArgfsX24. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 44 amino acids are replaced by 23 incorrect amino acids. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553599432; hg19: chr2-239975219;