rs12666612

Variant names:

• chr7-18335622-T-C
• rs12666612
• NM_001321868.2:c.26-160640T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001321868.2(HDAC9):​c.26-160640T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0866 in 151,638 control chromosomes in the GnomAD database, including 728 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.087 (728 hom., cov: 32)
• Consequence: HDAC9 NM_001321868.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.915
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC9	NM_001321868.2	c.26-160640T>C		intron_variant	Intron 2 of 25		NP_001308797.1
HDAC9	NM_001321869.2	c.26-160640T>C		intron_variant	Intron 2 of 12		NP_001308798.1
HDAC9	NM_001321870.2	c.26-160640T>C		intron_variant	Intron 2 of 12		NP_001308799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC9	ENST00000417496.6	c.26-123220T>C		intron_variant	Intron 2 of 12	2		ENSP00000401669.2
HDAC9	ENST00000707077.1	c.26-160640T>C		intron_variant	Intron 2 of 11			ENSP00000516728.1
HDAC9	ENST00000413509.6	c.-42+45107T>C		intron_variant	Intron 1 of 3	5		ENSP00000412497.2

Frequencies

GnomAD3 genomes AF: 0.0864 AC: 13094 AN: 151520 Hom.: 719 Cov.: 32

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0884

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0970

Gnomad OTH AF: 0.0851

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0866 AC: 13130 AN: 151638 Hom.: 728 Cov.: 32 AF XY: 0.0908 AC XY: 6729 AN XY: 74100

African (AFR) AF: 0.0367 AC: 1521 AN: 41466

American (AMR) AF: 0.119 AC: 1812 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 417 AN: 3454

East Asian (EAS) AF: 0.178 AC: 912 AN: 5124

South Asian (SAS) AF: 0.152 AC: 734 AN: 4826

European-Finnish (FIN) AF: 0.0884 AC: 937 AN: 10596

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0970 AC: 6565 AN: 67696

Other (OTH) AF: 0.0871 AC: 183 AN: 2102

Alfa AF: 0.0846 Hom.: 533

Bravo AF: 0.0857

Asia WGS AF: 0.166 AC: 576 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.76
DANN	Benign	0.55
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12666612; hg19: chr7-18375245;