chrX-48806443-C-T

Variant names:

• chrX-48806443-C-T
• rs73209760
• NM_006044.4:c.513C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006044.4(HDAC6):​c.513C>T​(p.Tyr171Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,187,066 control chromosomes in the GnomAD database, including 5 homozygotes. There are 1,053 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., 58 hem., cov: 23)
  • Exomes 𝑓: 0.0029 (4 hom. 995 hem.)
• Consequence: HDAC6 NM_006044.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.842
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant X-48806443-C-T is Benign according to our data. Variant chrX-48806443-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 717434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.842 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 58 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.513C>T	p.Tyr171Tyr	synonymous	Exon 7 of 29	NP_006035.2
	HDAC6	NM_001321225.2		c.555C>T	p.Tyr185Tyr	synonymous	Exon 8 of 30	NP_001308154.1	B4DZH6
	HDAC6	NM_001321226.2		c.513C>T	p.Tyr171Tyr	synonymous	Exon 7 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.513C>T	p.Tyr171Tyr	synonymous	Exon 7 of 29	ENSP00000334061.5	Q9UBN7-1
	HDAC6	ENST00000376619.7	TSL:1	c.513C>T	p.Tyr171Tyr	synonymous	Exon 7 of 29	ENSP00000365804.2	Q9UBN7-1
	HDAC6	ENST00000462730.5	TSL:1	c.*768C>T		3_prime_UTR	Exon 6 of 6	ENSP00000496727.1	Q9BRX7

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 231 AN: 112481 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000729

Gnomad FIN AF: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.00133

GnomAD2 exomes AF: 0.00152 AC: 279 AN: 183355 AF XY: 0.00139

Gnomad AFR exome AF: 0.000912

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00275

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00286 AC: 3076 AN: 1074531 Hom.: 4 Cov.: 26 AF XY: 0.00291 AC XY: 995 AN XY: 342159

African (AFR) AF: 0.000617 AC: 16 AN: 25914

American (AMR) AF: 0.000938 AC: 33 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.000104 AC: 2 AN: 19220

East Asian (EAS) AF: 0.00 AC: 0 AN: 30116

South Asian (SAS) AF: 0.000560 AC: 30 AN: 53582

European-Finnish (FIN) AF: 0.000370 AC: 15 AN: 40526

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4083

European-Non Finnish (NFE) AF: 0.00353 AC: 2893 AN: 820574

Other (OTH) AF: 0.00190 AC: 86 AN: 45340

GnomAD4 genome AF: 0.00205 AC: 231 AN: 112535 Hom.: 1 Cov.: 23 AF XY: 0.00167 AC XY: 58 AN XY: 34697

African (AFR) AF: 0.00116 AC: 36 AN: 31000

American (AMR) AF: 0.000280 AC: 3 AN: 10701

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.000731 AC: 2 AN: 2735

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6198

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

European-Non Finnish (NFE) AF: 0.00351 AC: 187 AN: 53221

Other (OTH) AF: 0.00131 AC: 2 AN: 1529

Alfa AF: 0.00225 Hom.: 21

Bravo AF: 0.00204

EpiCase AF: 0.00398

EpiControl AF: 0.00291

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	X-linked dominant chondrodysplasia, Chassaing-Lacombe type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.5
DANN	Benign	0.46
PhyloP100		0.84
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs73209760; hg19: chrX-48664850; COSMIC: COSV100491390; COSMIC: COSV100491390;