X-48802744-C-G

Position:

• chrX-48802744-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006044.4(HDAC6):​c.52C>G​(p.Gln18Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.983

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HDAC6. . Gene score misZ 3.2915 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked dominant chondrodysplasia, Chassaing-Lacombe type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.08280152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC6	NM_006044.4	c.52C>G	p.Gln18Glu	missense_variant	2/29	ENST00000334136.11	NP_006035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC6	ENST00000334136.11	c.52C>G	p.Gln18Glu	missense_variant	2/29	1	NM_006044.4	ENSP00000334061.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2024

The c.52C>G (p.Q18E) alteration is located in exon 2 (coding exon 1) of the HDAC6 gene. This alteration results from a C to G substitution at nucleotide position 52, causing the glutamine (Q) at amino acid position 18 to be replaced by a glutamic acid (E). 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	Benign	0.099
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.15	.;T;T;T;T;.;T;T;.;.;T;T;.;T;.
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.85	T;T;.;T;.;.;.;.;.;T;.;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;.;.;N;.;N;N;.;.;N;N;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.55	N;N;N;N;N;.;N;N;.;.;.;.;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.47	T;D;T;T;T;.;T;T;.;.;.;.;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;.;T;T;.;.;.;.;T;T;T
Polyphen		0.030, 0.015	.;.;.;.;B;B;B;B;B;.;B;B;B;.;.
Vest4		0.15, 0.12
MutPred		0.12		Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);Loss of MoRF binding (P = 0.0305);
MVP		0.50
MPC		0.97
ClinPred		0.045	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs950820471; hg19: chrX-48661151;