rs1557030620

Positions:

• chrX-48823058-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_006044.4(HDAC6):​c.2659T>C​(p.Phe887Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.767

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 -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=0.047596365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC6	NM_006044.4	c.2659T>C	p.Phe887Leu	missense_variant	25/29	ENST00000334136.11	NP_006035.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDAC6	ENST00000334136.11	c.2659T>C	p.Phe887Leu	missense_variant	25/29	1	NM_006044.4	ENSP00000334061	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jan 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.86
DANN	Benign	0.86
DEOGEN2	Benign	0.094	T;T;T;T;T;.
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.63	.;.;.;.;T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.048	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.63	N;.;N;.;.;.
REVEL	Benign	0.047
Sift	Benign	0.99	T;.;T;.;.;.
Sift4G	Benign	0.62	T;.;T;.;.;.
Polyphen		0.0010	B;B;B;B;B;.
Vest4		0.054
MutPred		0.32		Gain of MoRF binding (P = 0.1451);Gain of MoRF binding (P = 0.1451);Gain of MoRF binding (P = 0.1451);Gain of MoRF binding (P = 0.1451);Gain of MoRF binding (P = 0.1451);.;
MVP		0.27
MPC		0.069
ClinPred		0.033	T
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1557030620; hg19: chrX-48681468;