X-48806405-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Moderate BP6_Moderate BS2

The NM_006044.4(HDAC6):c.475A>C(p.Met159Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000901 in 1,198,471 control chromosomes in the GnomAD database, including 1 homozygotes. There are 46 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 0.000098 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.000089 (1 hom. 43 hem.)
• Consequence: HDAC6 NM_006044.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 8.02

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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HDAC6
• BP4: Computational evidence support a benign effect (MetaRNN=0.09432629).
• BP6: Variant X-48806405-A-C is Benign according to our data. Variant chrX-48806405-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 1206265.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-48806405-A-C is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC6	NM_006044.4	c.475A>C	p.Met159Leu	missense_variant	7/29	ENST00000334136.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC6	ENST00000334136.11	c.475A>C	p.Met159Leu	missense_variant	7/29	1	NM_006044.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000981 AC: 11 AN: 112149 Hom.: 0 Cov.: 24 AF XY: 0.0000874 AC XY: 3 AN XY: 34319

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000125 AC: 23 AN: 183436 Hom.: 0 AF XY: 0.000192 AC XY: 13 AN XY: 67874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000367

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000893 AC: 97 AN: 1086268 Hom.: 1 Cov.: 26 AF XY: 0.000122 AC XY: 43 AN XY: 352650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000830

Gnomad4 OTH exome AF: 0.0000656

GnomAD4 genome AF: 0.0000980 AC: 11 AN: 112203 Hom.: 0 Cov.: 24 AF XY: 0.0000873 AC XY: 3 AN XY: 34383

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000938

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000151

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000654

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	HDAC6: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Benign	0.94
DEOGEN2	Benign	0.17	T;T;T;T;T;T;T;.;T;.
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.094	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	0.89	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;N;N;N;N;.;.;.;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.74	T;T;T;T;T;.;.;.;D;T
Sift4G	Pathogenic	0.0	D;D;T;T;T;.;.;.;D;D
Polyphen		0.99	.;.;D;D;D;D;D;.;.;.
Vest4		0.14, 0.24
MutPred		0.56		Loss of catalytic residue at M159 (P = 0.0867);Loss of catalytic residue at M159 (P = 0.0867);Loss of catalytic residue at M159 (P = 0.0867);Loss of catalytic residue at M159 (P = 0.0867);Loss of catalytic residue at M159 (P = 0.0867);Loss of catalytic residue at M159 (P = 0.0867);Loss of catalytic residue at M159 (P = 0.0867);.;Loss of catalytic residue at M159 (P = 0.0867);Loss of catalytic residue at M159 (P = 0.0867);
MVP		0.93
MPC		1.5
ClinPred		0.25	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.85

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: rs372471896; hg19: chrX-48664812;