rs148220149

chrX-48823187-G-C

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.2788G>C(p.Gly930Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000537 in 1,205,258 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 194 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., 48 hem., cov: 23)
  • Exomes 𝑓: 0.00044 (0 hom. 146 hem.)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.855

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=0.0074141026).
• BP6: Variant X-48823187-G-C is Benign according to our data. Variant chrX-48823187-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 446055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-48823187-G-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 48 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC6	NM_006044.4	c.2788G>C	p.Gly930Arg	missense_variant	25/29	ENST00000334136.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC6	ENST00000334136.11	c.2788G>C	p.Gly930Arg	missense_variant	25/29	1	NM_006044.4	P2

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 171 AN: 111573 Hom.: 0 Cov.: 23 AF XY: 0.00142 AC XY: 48 AN XY: 33769

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00570

Gnomad ASJ AF: 0.00608

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000170

Gnomad OTH AF: 0.00668

GnomAD3 exomes AF: 0.000771 AC: 130 AN: 168672 Hom.: 0 AF XY: 0.000535 AC XY: 30 AN XY: 56030

Gnomad AFR exome AF: 0.00276

Gnomad AMR exome AF: 0.000725

Gnomad ASJ exome AF: 0.00726

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.00237

GnomAD4 exome AF: 0.000435 AC: 476 AN: 1093633 Hom.: 0 Cov.: 32 AF XY: 0.000406 AC XY: 146 AN XY: 359623

Gnomad4 AFR exome AF: 0.00323

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00882

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00153 AC: 171 AN: 111625 Hom.: 0 Cov.: 23 AF XY: 0.00142 AC XY: 48 AN XY: 33831

Gnomad4 AFR AF: 0.00247

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.00608

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000170

Gnomad4 OTH AF: 0.00659

Alfa AF: 0.000916 Hom.: 15

Bravo AF: 0.00251

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00313 AC: 12

ESP6500EA AF: 0.000595 AC: 4

ExAC AF: 0.000825 AC: 100

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 20, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	11
Dann	Benign	0.87
DEOGEN2	Benign	0.31	T;T;T;T;T;.
FATHMM_MKL	Benign	0.039	N
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.0074	T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.75	N;N;N;N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N;.;N;.;.;.
REVEL	Benign	0.095
Sift	Benign	0.17	T;.;T;.;.;.
Sift4G	Uncertain	0.039	D;.;D;.;.;.
Polyphen		0.24	B;B;B;B;B;.
Vest4		0.25
MutPred		0.36		Gain of methylation at G930 (P = 0.0374);Gain of methylation at G930 (P = 0.0374);Gain of methylation at G930 (P = 0.0374);Gain of methylation at G930 (P = 0.0374);Gain of methylation at G930 (P = 0.0374);.;
MVP		0.53
MPC		0.23
ClinPred		0.0092	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.071
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs148220149; hg19: chrX-48681597; COSMIC: COSV105221010; COSMIC: COSV105221010;