X-48803118-T-G

Variant names:

• chrX-48803118-T-G
• rs190360216
• NM_006044.4:c.223-10T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006044.4(HDAC6):​c.223-10T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,336 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts 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: 9.1e-7 (0 hom. 1 hem.)
• Consequence: HDAC6 NM_006044.4 intron
• Scores: Splicing: ADA: 0.00002810
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0470
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.223-10T>G		intron	N/A	NP_006035.2
	HDAC6	NM_001321225.2		c.265-10T>G		intron	N/A	NP_001308154.1	B4DZH6
	HDAC6	NM_001321226.2		c.223-10T>G		intron	N/A	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.223-10T>G		intron	N/A	ENSP00000334061.5	Q9UBN7-1
	HDAC6	ENST00000376619.7	TSL:1	c.223-10T>G		intron	N/A	ENSP00000365804.2	Q9UBN7-1
	HDAC6	ENST00000462730.5	TSL:1	c.223-10T>G		intron	N/A	ENSP00000496727.1	Q9BRX7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.15e-7 AC: 1 AN: 1093336 Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 1 AN XY: 359038

African (AFR) AF: 0.00 AC: 0 AN: 26290

American (AMR) AF: 0.00 AC: 0 AN: 34980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19329

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.0000187 AC: 1 AN: 53593

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4119

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 838481

Other (OTH) AF: 0.00 AC: 0 AN: 45913

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.9
DANN	Benign	0.71
PhyloP100		0.047

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.066
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: rs190360216; hg19: chrX-48661525;