X-48802925-G-A

Position:

• chrX-48802925-G-A

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.148G>A​(p.Val50Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,809 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.342

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=0.08310509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC6	NM_006044.4	c.148G>A	p.Val50Ile	missense_variant	3/29	ENST00000334136.11	NP_006035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC6	ENST00000334136.11	c.148G>A	p.Val50Ile	missense_variant	3/29	1	NM_006044.4	ENSP00000334061.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095809 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 1 AN XY: 361337

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

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

Jan 18, 2023

The c.148G>A (p.V50I) alteration is located in exon 3 (coding exon 2) of the HDAC6 gene. This alteration results from a G to A substitution at nucleotide position 148, causing the valine (V) at amino acid position 50 to be replaced by an isoleucine (I). 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	0.086
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.16	.;T;T;T;T;.;T;T;.;.;T;T;.;T;.
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.74	T;T;.;T;.;.;.;.;.;T;.;T;T;T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.083	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;.;.;.;L;.;L;L;.;.;L;L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.61	N;N;N;N;N;.;N;N;.;.;.;.;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.17	T;T;T;T;T;.;T;T;.;.;.;.;T;T;T
Sift4G	Benign	0.19	T;D;T;T;T;.;T;T;.;.;.;.;T;T;T
Polyphen		0.012, 0.15	.;.;.;.;B;B;B;B;B;.;B;B;B;.;.
Vest4		0.11, 0.13
MutPred		0.25		Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);Loss of methylation at K51 (P = 0.0722);
MVP		0.59
MPC		0.77
ClinPred		0.079	T
GERP RS		1.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.11
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2062751518; hg19: chrX-48661332;