X-48805638-T-G

Position:

• chrX-48805638-T-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.404T>G​(p.Phe135Cys) 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. 13/20 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)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.219

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=0.23806575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC6	NM_006044.4	c.404T>G	p.Phe135Cys	missense_variant	6/29	ENST00000334136.11	NP_006035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC6	ENST00000334136.11	c.404T>G	p.Phe135Cys	missense_variant	6/29	1	NM_006044.4	ENSP00000334061.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

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

Dec 07, 2024

The c.404T>G (p.F135C) alteration is located in exon 6 (coding exon 5) of the HDAC6 gene. This alteration results from a T to G substitution at nucleotide position 404, causing the phenylalanine (F) at amino acid position 135 to be replaced by a cysteine (C). 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	0.20
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.19	.;T;T;T;.;T;T;.;.;T;T;.;.;.;T;.
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.82	T;.;T;.;.;.;.;.;.;.;T;D;T;T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.17	.;.;.;N;.;N;N;.;.;N;N;.;.;.;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.5	D;D;D;N;.;D;N;.;.;.;.;D;.;.;D;D
REVEL	Benign	0.22
Sift	Benign	0.20	T;T;T;T;.;T;T;.;.;.;.;T;.;.;T;T
Sift4G	Uncertain	0.043	D;T;T;T;.;T;T;.;.;.;.;T;.;.;T;D
Polyphen		0.88, 0.99	.;.;.;P;D;P;P;D;.;P;P;D;.;.;.;.
Vest4		0.56, 0.51
MutPred		0.35		Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);.;Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);.;.;Gain of ubiquitination at K138 (P = 0.1181);Gain of ubiquitination at K138 (P = 0.1181);
MVP		0.73
MPC		2.2
ClinPred		0.39	T
GERP RS		1.7
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.13
gMVP		0.86

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-48664045;