7-18590357-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_178425.4(HDAC9):c.286A>G(p.Ile96Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,612,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: HDAC9 NM_178425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

Genes affected

HDAC9 (HGNC:14065): (histone deacetylase 9) 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 has sequence homology to members of the histone deacetylase family. This gene is orthologous to the Xenopus and mouse MITR genes. The MITR protein lacks the histone deacetylase catalytic domain. It represses MEF2 activity through recruitment of multicomponent corepressor complexes that include CtBP and HDACs. This encoded protein may play a role in hematopoiesis. Multiple alternatively spliced transcripts have been described for this gene but the full-length nature of some of them has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022714317).
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC9	NM_178425.4	c.286A>G	p.Ile96Val	missense_variant	4/26	ENST00000686413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC9	ENST00000686413.1	c.286A>G	p.Ile96Val	missense_variant	4/26		NM_178425.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000182 AC: 45 AN: 246692 Hom.: 0 AF XY: 0.000180 AC XY: 24 AN XY: 133682

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00168

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000931

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000945 AC: 138 AN: 1460244 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76 AN XY: 726178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000450

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000882

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.0000995

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74494

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.000149 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

The c.286A>G (p.I96V) alteration is located in exon 3 (coding exon 3) of the HDAC9 gene. This alteration results from a A to G substitution at nucleotide position 286, causing the isoleucine (I) at amino acid position 96 to be replaced by a valine (V). 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	0.089
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Benign	0.97
Eigen	Benign	-0.18
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D;T;T;D;D;T;D;D;D;T;T;D;D;D
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.023	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.11	N;N;N;N;.;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.089
Sift	Benign	0.066	T;T;T;T;.;T;T;T;T;T;T;T;D;T;T
Sift4G	Benign	0.51	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.11, 0.24, 0.15, 0.51	.;.;.;.;.;B;B;.;B;B;P;B;.;.;.
Vest4		0.44
MutPred		0.33		.;.;.;.;.;Gain of methylation at K94 (P = 0.0921);Gain of methylation at K94 (P = 0.0921);Gain of methylation at K94 (P = 0.0921);.;.;Gain of methylation at K94 (P = 0.0921);.;.;.;.;
MVP		0.41
MPC		0.40
ClinPred		0.081	T
GERP RS		5.8
Varity_R		0.075
gMVP		0.073

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200990910; hg19: chr7-18629980;