chr22-50246704-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032019.6(HDAC10):​c.1546C>T​(p.Arg516Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,611,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

HDAC10
NM_032019.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.156
Variant links:
Genes affected
HDAC10 (HGNC:18128): (histone deacetylase 10) The protein encoded by this gene belongs to the histone deacetylase family, members of which deacetylate lysine residues on the N-terminal part of the core histones. Histone deacetylation modulates chromatin structure, and plays an important role in transcriptional regulation, cell cycle progression, and developmental events. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]
MAPK12 (HGNC:6874): (mitogen-activated protein kinase 12) Activation of members of the mitogen-activated protein kinase family is a major mechanism for transduction of extracellular signals. Stress-activated protein kinases are one subclass of MAP kinases. The protein encoded by this gene functions as a signal transducer during differentiation of myoblasts to myotubes. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05326101).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HDAC10NM_032019.6 linkuse as main transcriptc.1546C>T p.Arg516Trp missense_variant 16/20 ENST00000216271.10
HDAC10NM_001159286.2 linkuse as main transcriptc.1486C>T p.Arg496Trp missense_variant 15/19

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HDAC10ENST00000216271.10 linkuse as main transcriptc.1546C>T p.Arg516Trp missense_variant 16/201 NM_032019.6 P1Q969S8-1
ENST00000685176.2 linkuse as main transcriptn.2068G>A non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
250732
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135710
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
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:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000199
AC:
29
AN:
1459530
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
13
AN XY:
726066
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000332
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152354
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.0000240
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.00000824
AC:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 22, 2023The c.1546C>T (p.R516W) alteration is located in exon 16 (coding exon 16) of the HDAC10 gene. This alteration results from a C to T substitution at nucleotide position 1546, causing the arginine (R) at amino acid position 516 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
0.10
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
19
DANN
Benign
0.94
DEOGEN2
Benign
0.046
T;T;.
Eigen
Benign
-0.85
Eigen_PC
Benign
-0.84
FATHMM_MKL
Benign
0.049
N
LIST_S2
Benign
0.80
T;T;T
M_CAP
Benign
0.0086
T
MetaRNN
Benign
0.053
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.4
L;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.039
Sift
Benign
0.089
T;T;T
Sift4G
Benign
0.13
T;D;D
Polyphen
0.0070
B;B;B
Vest4
0.29
MutPred
0.50
Loss of disorder (P = 0.0157);.;.;
MVP
0.51
MPC
0.054
ClinPred
0.044
T
GERP RS
-2.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.044
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs544861577; hg19: chr22-50685133; COSMIC: COSV50536812; COSMIC: COSV50536812; API