X-48802784-C-T

Variant names:

• chrX-48802784-C-T
• rs141268593
• NM_006044.4:c.92C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006044.4(HDAC6):​c.92C>T​(p.Ser31Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,205,018 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S31W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000037 (0 hom. 11 hem.)
• Consequence: HDAC6 NM_006044.4 missense, splice_region
• Scores: Splicing: ADA: 0.001112
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.323
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015642107).
• BS2: High Hemizygotes in GnomAd4 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.92C>T	p.Ser31Leu	missense splice_region	Exon 2 of 29	NP_006035.2
	HDAC6	NM_001321225.2		c.134C>T	p.Ser45Leu	missense splice_region	Exon 3 of 30	NP_001308154.1	B4DZH6
	HDAC6	NM_001321226.2		c.92C>T	p.Ser31Leu	missense splice_region	Exon 2 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.92C>T	p.Ser31Leu	missense splice_region	Exon 2 of 29	ENSP00000334061.5	Q9UBN7-1
	HDAC6	ENST00000376619.7	TSL:1	c.92C>T	p.Ser31Leu	missense splice_region	Exon 2 of 29	ENSP00000365804.2	Q9UBN7-1
	HDAC6	ENST00000462730.5	TSL:1	c.92C>T	p.Ser31Leu	missense splice_region	Exon 2 of 6	ENSP00000496727.1	Q9BRX7

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 13 AN: 111676 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000473

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: 0.0000754

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000589 AC: 10 AN: 169871 AF XY: 0.0000710

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0000758

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000680

Gnomad NFE exome AF: 0.0000402

Gnomad OTH exome AF: 0.000236

GnomAD4 exome AF: 0.0000366 AC: 40 AN: 1093288 Hom.: 0 Cov.: 31 AF XY: 0.0000306 AC XY: 11 AN XY: 359250

African (AFR) AF: 0.000190 AC: 5 AN: 26305

American (AMR) AF: 0.0000866 AC: 3 AN: 34654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19297

East Asian (EAS) AF: 0.00 AC: 0 AN: 30007

South Asian (SAS) AF: 0.00 AC: 0 AN: 53231

European-Finnish (FIN) AF: 0.0000996 AC: 4 AN: 40171

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.0000298 AC: 25 AN: 839585

Other (OTH) AF: 0.0000653 AC: 3 AN: 45908

GnomAD4 genome AF: 0.000116 AC: 13 AN: 111730 Hom.: 0 Cov.: 23 AF XY: 0.0000590 AC XY: 2 AN XY: 33906

African (AFR) AF: 0.000130 AC: 4 AN: 30784

American (AMR) AF: 0.000473 AC: 5 AN: 10577

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3552

South Asian (SAS) AF: 0.00 AC: 0 AN: 2684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000754 AC: 4 AN: 53057

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000825 AC: 10

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.082
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Benign	0.76
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.32
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.038
Sift	Benign	0.70	T
Sift4G	Benign	0.24	T
Polyphen		0.0020	B
Vest4		0.060
MVP		0.49
MPC		0.81
ClinPred		0.015	T
GERP RS		1.5
PromoterAI		-0.071	Neutral
Varity_R		0.055
gMVP		0.43
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.12		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: rs141268593; hg19: chrX-48661191; COSMIC: COSV61928309; COSMIC: COSV61928309;