Genetic Variant HDAC11:p.Arg221Trp (chr3-13504105-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024827.4(HDAC11):c.661C>T(p.Arg221Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,780 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R221Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

HDAC11
NM_024827.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.923

Variant links:

Genes affected

HDAC11 (HGNC:19086): (histone deacetylase 11) This gene encodes a class IV histone deacetylase. The encoded protein is localized to the nucleus and may be involved in regulating the expression of interleukin 10. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Apr 2009]

HDAC11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC11	NM_024827.4 link	c.661C>T	p.Arg221Trp	missense_variant	Exon 9 of 10	ENST00000295757.8	NP_079103.2	Q96DB2-1
HDAC11	NM_001136041.3 link	c.508C>T	p.Arg170Trp	missense_variant	Exon 9 of 10		NP_001129513.1	Q96DB2-2
HDAC11	NM_001330636.2 link	c.424C>T	p.Arg142Trp	missense_variant	Exon 6 of 7		NP_001317565.1	B5MCQ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC11	ENST00000295757.8 link	c.661C>T	p.Arg221Trp	missense_variant	Exon 9 of 10	1	NM_024827.4	ENSP00000295757.3		Q96DB2-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000439

AC:

AN:

250532

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135622

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000972

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000616

AC:

AN:

1461624

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000728

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 07, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.661C>T (p.R221W) alteration is located in exon 9 (coding exon 9) of the HDAC11 gene. This alteration results from a C to T substitution at nucleotide position 661, causing the arginine (R) at amino acid position 221 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.075

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;T;T;T;.;.

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.62

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.72

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.044

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.2

D;D;D;D;D;D;D

REVEL

Pathogenic

0.66

Sift4G

Uncertain

0.039

.;.;.;.;D;T;T

Polyphen

1.0

D;.;.;.;.;.;.

Vest4

0.83

MutPred

0.60

Gain of ubiquitination at K216 (P = 0.0495);.;.;.;.;.;.;

MVP

0.85

MPC

1.2

ClinPred

0.91

GERP RS

2.7

Varity_R

0.80

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over