7-18634723-C-T

Variant names:

• chr7-18634723-C-T
• rs765515793
• NM_178425.4:c.893C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_178425.4(HDAC9):​c.893C>T​(p.Pro298Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,442,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: HDAC9 NM_178425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33
• Publications: 2 publications found

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]

HDAC9 Gene-Disease associations (from GenCC):

• auriculocondylar syndrome 4

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31487453).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178425.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC9	NM_178425.4	MANE Select	c.893C>T	p.Pro298Leu	missense	Exon 8 of 26	NP_848512.1	Q9UKV0-7
	HDAC9	NM_178423.3		c.884C>T	p.Pro295Leu	missense	Exon 8 of 26	NP_848510.1	Q9UKV0-5
	HDAC9	NM_001321868.2		c.818C>T	p.Pro273Leu	missense	Exon 8 of 26	NP_001308797.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC9	ENST00000686413.1	MANE Select	c.893C>T	p.Pro298Leu	missense	Exon 8 of 26	ENSP00000509161.1	Q9UKV0-7
	HDAC9	ENST00000441542.7	TSL:1	c.893C>T	p.Pro298Leu	missense	Exon 7 of 25	ENSP00000408617.2	Q9UKV0-7
	HDAC9	ENST00000406451.8	TSL:1	c.884C>T	p.Pro295Leu	missense	Exon 8 of 26	ENSP00000384657.3	Q9UKV0-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000408 AC: 9 AN: 220714 AF XY: 0.0000337

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000156

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000308

Gnomad OTH exome AF: 0.000182

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1442380 Hom.: 0 Cov.: 29 AF XY: 0.00000978 AC XY: 7 AN XY: 715700

African (AFR) AF: 0.00 AC: 0 AN: 33036

American (AMR) AF: 0.000140 AC: 6 AN: 42716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 38974

South Asian (SAS) AF: 0.00 AC: 0 AN: 83052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000636 AC: 7 AN: 1101190

Other (OTH) AF: 0.0000503 AC: 3 AN: 59672

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000659 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.13
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.70	P
Vest4		0.57
MVP		0.60
MPC		0.54
ClinPred		0.20	T
GERP RS		5.7
Varity_R		0.066
gMVP		0.31
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765515793; hg19: chr7-18674346;