X-48806463-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006044.4(HDAC6):​c.533C>T​(p.Pro178Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000381 in 1,049,887 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 0.0000038 ( 0 hom. 1 hem. )

Consequence

HDAC6
NM_006044.4 missense, splice_region

Scores

9
5
3
Splicing: ADA: 0.8825
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.96
Variant links:
Genes affected
HDAC6 (HGNC:14064): (histone deacetylase 6) 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 contains an internal duplication of two catalytic domains which appear to function independently of each other. This protein possesses histone deacetylase activity and represses transcription. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.877

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HDAC6NM_006044.4 linkc.533C>T p.Pro178Leu missense_variant, splice_region_variant Exon 7 of 29 ENST00000334136.11 NP_006035.2 Q9UBN7-1A0A024QZ26Q9NSW6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HDAC6ENST00000334136.11 linkc.533C>T p.Pro178Leu missense_variant, splice_region_variant Exon 7 of 29 1 NM_006044.4 ENSP00000334061.5 Q9UBN7-1

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
0.00000381
AC:
4
AN:
1049887
Hom.:
0
Cov.:
24
AF XY:
0.00000311
AC XY:
1
AN XY:
321853
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000376
Gnomad4 OTH exome
AF:
0.0000225
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Feb 08, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.533C>T (p.P178L) alteration is located in exon 7 (coding exon 6) of the HDAC6 gene. This alteration results from a C to T substitution at nucleotide position 533, causing the proline (P) at amino acid position 178 to be replaced by a leucine (L). 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
Uncertain
0.49
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;T;D;D;D;D;D;.
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.82
.;T;.;.;.;.;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.88
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.22
D
MutationAssessor
Pathogenic
3.2
.;.;M;M;M;M;M;.
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-9.0
D;D;D;D;D;.;.;.
REVEL
Pathogenic
0.71
Sift
Pathogenic
0.0
D;D;D;D;D;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;.;.;.
Polyphen
1.0
.;.;D;D;D;D;D;.
Vest4
0.71, 0.72
MutPred
0.62
Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;
MVP
0.93
MPC
2.1
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.73
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.88
dbscSNV1_RF
Benign
0.67
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: chrX-48664870; COSMIC: COSV61927435; COSMIC: COSV61927435; API