7-18647822-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_178425.4(HDAC9):c.1073C>T(p.Thr358Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000869 in 1,611,630 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 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: HDAC9 NM_178425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12253091).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC9	NM_178425.4	c.1073C>T	p.Thr358Met	missense_variant	10/26	ENST00000686413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC9	ENST00000686413.1	c.1073C>T	p.Thr358Met	missense_variant	10/26		NM_178425.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000122 AC: 30 AN: 244908 Hom.: 0 AF XY: 0.000136 AC XY: 18 AN XY: 132780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000341

Gnomad SAS exome AF: 0.000497

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000633

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000925 AC: 135 AN: 1459486 Hom.: 0 Cov.: 31 AF XY: 0.0000937 AC XY: 68 AN XY: 725830

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000675

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000373

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000810

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74306

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000132 AC: 16

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

Apr 17, 2023

The c.1073C>T (p.T358M) alteration is located in exon 9 (coding exon 9) of the HDAC9 gene. This alteration results from a C to T substitution at nucleotide position 1073, causing the threonine (T) at amino acid position 358 to be replaced by a methionine (M). 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	0.072
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.063
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.57	D;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.21	N;.;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.049
Sift	Benign	0.080	T;.;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.98, 0.99, 0.98, 1.0, 0.97	.;.;D;D;.;D;D;D;D;.;.
Vest4		0.54
MVP		0.56
MPC		0.63
ClinPred		0.042	T
GERP RS		3.9
Varity_R		0.029
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs367766754; hg19: chr7-18687445; COSMIC: COSV67786225;