X-48805666-T-C

Variant names:

• chrX-48805666-T-C
• rs143689285
• NM_006044.4:c.432T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_006044.4(HDAC6):​c.432T>C​(p.Val144Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00109 in 1,169,544 control chromosomes in the GnomAD database, including 7 homozygotes. There are 324 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (3 hom., 154 hem., cov: 23)
  • Exomes 𝑓: 0.00061 (4 hom. 170 hem.)
• Consequence: HDAC6 NM_006044.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.97
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-48805666-T-C is Benign according to our data. Variant chrX-48805666-T-C is described in ClinVar as Benign. ClinVar VariationId is 731665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.97 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00562 (630/112103) while in subpopulation AFR AF = 0.0193 (594/30849). AF 95% confidence interval is 0.018. There are 3 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.432T>C	p.Val144Val	synonymous	Exon 6 of 29	NP_006035.2
	HDAC6	NM_001321225.2		c.474T>C	p.Val158Val	synonymous	Exon 7 of 30	NP_001308154.1	B4DZH6
	HDAC6	NM_001321226.2		c.432T>C	p.Val144Val	synonymous	Exon 6 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.432T>C	p.Val144Val	synonymous	Exon 6 of 29	ENSP00000334061.5	Q9UBN7-1
	HDAC6	ENST00000376619.7	TSL:1	c.432T>C	p.Val144Val	synonymous	Exon 6 of 29	ENSP00000365804.2	Q9UBN7-1
	HDAC6	ENST00000462730.5	TSL:1	c.432T>C	p.Val144Val	synonymous	Exon 6 of 6	ENSP00000496727.1	Q9BRX7

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 630 AN: 112050 Hom.: 3 Cov.: 23

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

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: 0.0000565

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00136 AC: 167 AN: 122685 AF XY: 0.00104

Gnomad AFR exome AF: 0.0184

Gnomad AMR exome AF: 0.000741

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000579

GnomAD4 exome AF: 0.000610 AC: 645 AN: 1057441 Hom.: 4 Cov.: 29 AF XY: 0.000495 AC XY: 170 AN XY: 343197

African (AFR) AF: 0.0203 AC: 512 AN: 25229

American (AMR) AF: 0.000797 AC: 23 AN: 28852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18687

East Asian (EAS) AF: 0.00 AC: 0 AN: 27893

South Asian (SAS) AF: 0.0000200 AC: 1 AN: 50120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38133

Middle Eastern (MID) AF: 0.00122 AC: 5 AN: 4088

European-Non Finnish (NFE) AF: 0.0000390 AC: 32 AN: 819852

Other (OTH) AF: 0.00161 AC: 72 AN: 44587

GnomAD4 genome AF: 0.00562 AC: 630 AN: 112103 Hom.: 3 Cov.: 23 AF XY: 0.00449 AC XY: 154 AN XY: 34277

African (AFR) AF: 0.0193 AC: 594 AN: 30849

American (AMR) AF: 0.00235 AC: 25 AN: 10636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53097

Other (OTH) AF: 0.00519 AC: 8 AN: 1540

Alfa AF: 0.00290 Hom.: 21

Bravo AF: 0.00679

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	HDAC6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.6
DANN	Benign	0.87
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs143689285; hg19: chrX-48664073;