X-48806463-C-T

Variant names:

• chrX-48806463-C-T
• NM_006044.4:c.533C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_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: Splicing: ADA: 0.8825
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

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]

ACMG classification

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
HDAC6	NM_006044.4	c.533C>T	p.Pro178Leu	missense_variant, splice_region_variant	Exon 7 of 29	ENST00000334136.11	NP_006035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC6	ENST00000334136.11	c.533C>T	p.Pro178Leu	missense_variant, splice_region_variant	Exon 7 of 29	1	NM_006044.4	ENSP00000334061.5

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

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

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;