7-18629459-G-C

Variant names:

• chr7-18629459-G-C
• rs1181444955
• NM_178425.4:c.774G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178425.4(HDAC9):​c.774G>C​(p.Lys258Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HDAC9 NM_178425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.774G>C	p.Lys258Asn	missense	Exon 7 of 26	NP_848512.1	Q9UKV0-7
	HDAC9	NM_178423.3		c.765G>C	p.Lys255Asn	missense	Exon 7 of 26	NP_848510.1	Q9UKV0-5
	HDAC9	NM_058176.2		c.765G>C	p.Lys255Asn	missense	Exon 6 of 23	NP_478056.1	Q9UKV0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC9	ENST00000686413.1	MANE Select	c.774G>C	p.Lys258Asn	missense	Exon 7 of 26	ENSP00000509161.1	Q9UKV0-7
	HDAC9	ENST00000441542.7	TSL:1	c.774G>C	p.Lys258Asn	missense	Exon 6 of 25	ENSP00000408617.2	Q9UKV0-7
	HDAC9	ENST00000406451.8	TSL:1	c.765G>C	p.Lys255Asn	missense	Exon 7 of 26	ENSP00000384657.3	Q9UKV0-5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248290 AF XY: 0.00

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460166 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726380

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110882

Other (OTH) AF: 0.00 AC: 0 AN: 60282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.028	B
Vest4		0.78
MutPred		0.35		Loss of methylation at K255 (P = 0.0012)
MVP		0.80
MPC		0.89
ClinPred		0.94	D
GERP RS		5.1
Varity_R		0.52
gMVP		0.45
Mutation Taster		=58/42	polymorphism

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

Other links and lift over

dbSNP: rs1181444955; hg19: chr7-18669082;