rs367767249

Variant names:

• chrX-48823531-A-G
• rs367767249
• NM_006044.4:c.3132A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006044.4(HDAC6):​c.3132A>G​(p.Ile1044Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,208,169 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 237 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 7 hem., cov: 22)
  • Exomes 𝑓: 0.00064 (0 hom. 230 hem.)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0900
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03717178).
• BP6: Variant X-48823531-A-G is Benign according to our data. Variant chrX-48823531-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445380.
• BS2: High Hemizygotes in GnomAd4 at 7 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.3132A>G	p.Ile1044Met	missense	Exon 25 of 29	NP_006035.2
	HDAC6	NM_001321225.2		c.3174A>G	p.Ile1058Met	missense	Exon 26 of 30	NP_001308154.1	B4DZH6
	HDAC6	NM_001321226.2		c.3132A>G	p.Ile1044Met	missense	Exon 25 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.3132A>G	p.Ile1044Met	missense	Exon 25 of 29	ENSP00000334061.5	Q9UBN7-1
	HDAC6	ENST00000376619.7	TSL:1	c.3132A>G	p.Ile1044Met	missense	Exon 25 of 29	ENSP00000365804.2	Q9UBN7-1
	HDAC6	ENST00000477528.5	TSL:1	n.3946A>G		non_coding_transcript_exon	Exon 24 of 28

Frequencies

GnomAD3 genomes AF: 0.000261 AC: 29 AN: 111313 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000381

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000416

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000297 AC: 53 AN: 178710 AF XY: 0.000219

Gnomad AFR exome AF: 0.000237

Gnomad AMR exome AF: 0.0000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000593

Gnomad OTH exome AF: 0.000452

GnomAD4 exome AF: 0.000639 AC: 701 AN: 1096856 Hom.: 0 Cov.: 32 AF XY: 0.000635 AC XY: 230 AN XY: 362284

African (AFR) AF: 0.0000379 AC: 1 AN: 26377

American (AMR) AF: 0.000114 AC: 4 AN: 35148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19336

East Asian (EAS) AF: 0.00 AC: 0 AN: 30169

South Asian (SAS) AF: 0.00 AC: 0 AN: 53863

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40374

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4135

European-Non Finnish (NFE) AF: 0.000782 AC: 658 AN: 841414

Other (OTH) AF: 0.000695 AC: 32 AN: 46040

GnomAD4 genome AF: 0.000261 AC: 29 AN: 111313 Hom.: 0 Cov.: 22 AF XY: 0.000209 AC XY: 7 AN XY: 33499

African (AFR) AF: 0.0000980 AC: 3 AN: 30606

American (AMR) AF: 0.000381 AC: 4 AN: 10486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3533

South Asian (SAS) AF: 0.00 AC: 0 AN: 2615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000416 AC: 22 AN: 52929

Other (OTH) AF: 0.00 AC: 0 AN: 1506

Alfa AF: 0.000391 Hom.: 2

Bravo AF: 0.000280

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000264 AC: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	4.4
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.090
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.033
Sift	Uncertain	0.020	D
Sift4G	Benign	0.14	T
Polyphen		0.40	B
Vest4		0.12
MVP		0.54
MPC		0.088
ClinPred		0.0050	T
GERP RS		2.8
PromoterAI		0.0064	Neutral
Varity_R		0.12
gMVP		0.10
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs367767249; hg19: chrX-48681941; COSMIC: COSV61930587; COSMIC: COSV61930587;