chrX-48802955-G-A

Position:

• chrX-48802955-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_006044.4(HDAC6):​c.178G>A​(p.Gly60Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,096,994 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.11

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 Benign. Variant got -7 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=0.038683146).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDAC6	NM_006044.4	c.178G>A	p.Gly60Ser	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.178G>A	p.Gly60Ser	missense_variant	3/29	1	NM_006044.4	ENSP00000334061.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1096994 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 2 AN XY: 362420

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: 0.00000713

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.6
DANN	Benign	0.83
DEOGEN2	Benign	0.092	.;T;T;T;.;T;T;.;.;T;T;.;.;.;T;.
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.75	T;.;T;.;.;.;.;.;.;.;T;T;T;T;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.039	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.48	.;.;.;N;.;N;N;.;.;N;N;.;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.12	N;N;N;N;.;N;N;.;.;.;.;N;.;.;N;N
REVEL	Benign	0.040
Sift	Benign	1.0	T;T;T;T;.;T;T;.;.;.;.;T;.;.;T;T
Sift4G	Benign	1.0	T;T;T;T;.;T;T;.;.;.;.;T;.;.;T;T
Polyphen		0.0050, 0.013	.;.;.;B;B;B;B;B;.;B;B;B;.;.;.;.
Vest4		0.087, 0.084
MutPred		0.30		Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);.;Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);.;.;Gain of phosphorylation at G60 (P = 0.0615);Gain of phosphorylation at G60 (P = 0.0615);
MVP		0.38
MPC		0.90
ClinPred		0.043	T
GERP RS		3.3
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.053
gMVP		0.19

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: rs1236426492; hg19: chrX-48661362; COSMIC: COSV61931003; COSMIC: COSV61931003;