rs41312114

chrX-48823730-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_006044.4(HDAC6):c.3248G>A(p.Gly1083Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00328 in 1,208,599 control chromosomes in the GnomAD database, including 6 homozygotes. There are 1,217 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 0.0020 (0 hom., 57 hem., cov: 22)
  • Exomes 𝑓: 0.0034 (6 hom. 1160 hem.)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.33

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HDAC6
• BP4: Computational evidence support a benign effect (MetaRNN=0.010107607).
• BP6: Variant X-48823730-G-A is Benign according to our data. Variant chrX-48823730-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48823730-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 57 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC6	NM_006044.4	c.3248G>A	p.Gly1083Asp	missense_variant	26/29	ENST00000334136.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC6	ENST00000334136.11	c.3248G>A	p.Gly1083Asp	missense_variant	26/29	1	NM_006044.4	P2

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 222 AN: 111609 Hom.: 0 Cov.: 22 AF XY: 0.00169 AC XY: 57 AN XY: 33763

Gnomad AFR AF: 0.000326

Gnomad AMI AF: 0.00441

Gnomad AMR AF: 0.000190

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: 0.00390

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00169 AC: 304 AN: 179820 Hom.: 0 AF XY: 0.00152 AC XY: 98 AN XY: 64574

Gnomad AFR exome AF: 0.000620

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00360

Gnomad OTH exome AF: 0.00112

GnomAD4 exome AF: 0.00341 AC: 3744 AN: 1096941 Hom.: 6 Cov.: 30 AF XY: 0.00320 AC XY: 1160 AN XY: 362359

Gnomad4 AFR exome AF: 0.000493

Gnomad4 AMR exome AF: 0.0000569

Gnomad4 ASJ exome AF: 0.000207

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.00433

Gnomad4 OTH exome AF: 0.00165

GnomAD4 genome AF: 0.00199 AC: 222 AN: 111658 Hom.: 0 Cov.: 22 AF XY: 0.00169 AC XY: 57 AN XY: 33822

Gnomad4 AFR AF: 0.000326

Gnomad4 AMR AF: 0.000190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00390

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00298 Hom.: 118

Bravo AF: 0.00179

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00623 AC: 18

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00342 AC: 23

ExAC AF: 0.00187 AC: 227

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 22, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

HDAC6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 19, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T;T;T;.
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;.
MutationTaster	Benign	0.55	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.2	N;.;N;.;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.15	T;.;T;.;.;.
Sift4G	Uncertain	0.029	D;.;D;.;.;.
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.59
MVP		0.82
MPC		0.39
ClinPred		0.030	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.33
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41312114; hg19: chrX-48682140;