X-48806426-G-T

Position:

• chrX-48806426-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_006044.4(HDAC6):​c.496G>T​(p.Val166Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000645 in 1,084,756 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000065 (0 hom. 3 hem.)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.349

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 Likely_benign. Variant got -5 ACMG points.

• 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=0.13993415).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC6	NM_006044.4	c.496G>T	p.Val166Phe	missense_variant	7/29	ENST00000334136.11	NP_006035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC6	ENST00000334136.11	c.496G>T	p.Val166Phe	missense_variant	7/29	1	NM_006044.4	ENSP00000334061.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000645 AC: 7 AN: 1084756 Hom.: 0 Cov.: 26 AF XY: 0.00000855 AC XY: 3 AN XY: 350976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000199

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

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

Jul 02, 2024

The c.496G>T (p.V166F) alteration is located in exon 7 (coding exon 6) of the HDAC6 gene. This alteration results from a G to T substitution at nucleotide position 496, causing the valine (V) at amino acid position 166 to be replaced by a phenylalanine (F). 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	0.090
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;T;T;T;T;T;.;T;.
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.81	.;T;.;.;.;.;T;T;T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.33	.;.;N;N;N;N;N;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N;N;N;N;N;.;.;.;N;N
REVEL	Benign	0.14
Sift	Benign	0.052	T;T;T;D;T;.;.;.;D;T
Sift4G	Benign	0.071	T;T;T;T;T;.;.;.;D;D
Polyphen		0.84	.;.;P;P;P;P;P;.;.;.
Vest4		0.20, 0.20
MutPred		0.47		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);
MVP		0.58
MPC		1.8
ClinPred		0.37	T
GERP RS		-2.0
Varity_R		0.14
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2062817961; hg19: chrX-48664833;