X-48802955-G-A

Variant names:

• chrX-48802955-G-A
• rs1236426492
• NM_006044.4:c.178G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• 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
• Publications: 0 publications found

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]

HDAC6 Gene-Disease associations (from GenCC):

• X-linked dominant chondrodysplasia, Chassaing-Lacombe type

  Inheritance: XL Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038683146).
• BP6: Variant X-48802955-G-A is Benign according to our data. Variant chrX-48802955-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3524449.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006044.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC6	NM_006044.4	MANE Select	c.178G>A	p.Gly60Ser	missense	Exon 3 of 29	NP_006035.2
	HDAC6	NM_001321225.2		c.220G>A	p.Gly74Ser	missense	Exon 4 of 30	NP_001308154.1	B4DZH6
	HDAC6	NM_001321226.2		c.178G>A	p.Gly60Ser	missense	Exon 3 of 29	NP_001308155.1	Q9UBN7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC6	ENST00000334136.11	TSL:1 MANE Select	c.178G>A	p.Gly60Ser	missense	Exon 3 of 29	ENSP00000334061.5	Q9UBN7-1
	HDAC6	ENST00000376619.7	TSL:1	c.178G>A	p.Gly60Ser	missense	Exon 3 of 29	ENSP00000365804.2	Q9UBN7-1
	HDAC6	ENST00000462730.5	TSL:1	c.178G>A	p.Gly60Ser	missense	Exon 3 of 6	ENSP00000496727.1	Q9BRX7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000558 AC: 1 AN: 179082 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 26382

American (AMR) AF: 0.00 AC: 0 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19362

East Asian (EAS) AF: 0.00 AC: 0 AN: 30165

South Asian (SAS) AF: 0.00 AC: 0 AN: 53875

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40461

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841424

Other (OTH) AF: 0.00 AC: 0 AN: 46058

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.48	N
PhyloP100		2.1
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.040
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	B
Vest4		0.087
MutPred		0.30		Gain of phosphorylation at G60 (P = 0.0615)
MVP		0.38
MPC		0.90
ClinPred		0.043	T
GERP RS		3.3
PromoterAI		-0.0097	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.7
Varity_R		0.053
gMVP		0.19
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

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