2-239053523-TCGTTCTCGCAAGTCTGAGCCTCGATCAGAGAA-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001378414.1(HDAC4):​c.3135_3166delTTCTCTGATCGAGGCTCAGACTTGCGAGAACG​(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 (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

HDAC4
NM_001378414.1 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.73
Variant links:
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]

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HDAC4NM_001378414.1 linkc.3135_3166delTTCTCTGATCGAGGCTCAGACTTGCGAGAACG p.Ser1046ArgfsTer24 frameshift_variant Exon 26 of 27 ENST00000543185.6 NP_001365343.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HDAC4ENST00000543185.6 linkc.3135_3166delTTCTCTGATCGAGGCTCAGACTTGCGAGAACG p.Ser1046ArgfsTer24 frameshift_variant Exon 26 of 27 5 NM_001378414.1 ENSP00000440481.3 A0A7I2SVS4
HDAC4ENST00000345617.7 linkc.3120_3151delTTCTCTGATCGAGGCTCAGACTTGCGAGAACG p.Ser1041ArgfsTer24 frameshift_variant Exon 26 of 27 1 ENSP00000264606.3 P56524-1
HDAC4ENST00000430200.1 linkc.390_421delTTCTCTGATCGAGGCTCAGACTTGCGAGAACG p.Ser131fs frameshift_variant Exon 3 of 4 3 ENSP00000410551.1 H7C397
HDAC4ENST00000690129.1 linkn.1149_1180delTTCTCTGATCGAGGCTCAGACTTGCGAGAACG non_coding_transcript_exon_variant Exon 9 of 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
LINK: link

Submissions by phenotype

not provided Uncertain:1
Mar 15, 2018
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553599432; hg19: chr2-239975219; API