2-239053467-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BS1_SupportingBS2
The NM_001378414.1(HDAC4):c.3223G>A(p.Glu1075Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
HDAC4
NM_001378414.1 missense
NM_001378414.1 missense
Scores
1
3
15
Clinical Significance
Conservation
PhyloP100: 4.97
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 made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, HDAC4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.2810664).
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000233 (34/1460506) while in subpopulation MID AF= 0.000348 (2/5744). AF 95% confidence interval is 0.0000771. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High AC in GnomAd at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HDAC4 | NM_001378414.1 | c.3223G>A | p.Glu1075Lys | missense_variant | 26/27 | ENST00000543185.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HDAC4 | ENST00000543185.6 | c.3223G>A | p.Glu1075Lys | missense_variant | 26/27 | 5 | NM_001378414.1 | A1 | |
HDAC4 | ENST00000345617.7 | c.3208G>A | p.Glu1070Lys | missense_variant | 26/27 | 1 | P4 | ||
HDAC4 | ENST00000430200.1 | c.481G>A | p.Glu161Lys | missense_variant | 3/4 | 3 | |||
HDAC4 | ENST00000690129.1 | n.1237G>A | non_coding_transcript_exon_variant | 9/10 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152228Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000280 AC: 7AN: 249982Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135304
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GnomAD4 exome AF: 0.0000233 AC: 34AN: 1460506Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 726476
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GnomAD4 genome ? AF: 0.0000656 AC: 10AN: 152346Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74492
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2022 | The c.3208G>A (p.E1070K) 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 3208, causing the glutamic acid (E) at amino acid position 1070 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.
REVEL
Benign
Sift
Benign
T;.
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at