chrX-48806463-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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]

HDAC6 Gene-Disease associations (from GenCC):

• X-linked dominant chondrodysplasia, Chassaing-Lacombe type

  Inheritance: XL Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006044.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC6	NM_006044.4	MANE Select	c.533C>T	p.Pro178Leu	missense splice_region	Exon 7 of 29	NP_006035.2
	HDAC6	NM_001321225.2		c.575C>T	p.Pro192Leu	missense splice_region	Exon 8 of 30	NP_001308154.1	B4DZH6
	HDAC6	NM_001321226.2		c.533C>T	p.Pro178Leu	missense splice_region	Exon 7 of 29	NP_001308155.1	Q9UBN7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC6	ENST00000334136.11	TSL:1 MANE Select	c.533C>T	p.Pro178Leu	missense splice_region	Exon 7 of 29	ENSP00000334061.5	Q9UBN7-1
	HDAC6	ENST00000376619.7	TSL:1	c.533C>T	p.Pro178Leu	missense splice_region	Exon 7 of 29	ENSP00000365804.2	Q9UBN7-1
	HDAC6	ENST00000462730.5	TSL:1	c.*788C>T		3_prime_UTR	Exon 6 of 6	ENSP00000496727.1	Q9BRX7

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

African (AFR) AF: 0.00 AC: 0 AN: 25495

American (AMR) AF: 0.00 AC: 0 AN: 35150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19097

East Asian (EAS) AF: 0.00 AC: 0 AN: 30002

South Asian (SAS) AF: 0.00 AC: 0 AN: 52995

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4018

European-Non Finnish (NFE) AF: 0.00000376 AC: 3 AN: 798081

Other (OTH) AF: 0.0000225 AC: 1 AN: 44527

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-9.0	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.62		Gain of sheet (P = 0.0477)
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		-0.0064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.91
Mutation Taster		=45/55	disease causing

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

Other links and lift over

hg19: chrX-48664870; COSMIC: COSV61927435; COSMIC: COSV61927435;