rs3814991

Variant names:

• chr7-18595280-T-C
• rs3814991
• NM_178425.4:c.664+1251T>C

Variant summary

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

The NM_178425.4(HDAC9):​c.664+1251T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,100 control chromosomes in the GnomAD database, including 1,082 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 0.10 (1082 hom., cov: 33)
• Consequence: HDAC9 NM_178425.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.165
• Publications: 10 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC9	NM_178425.4	c.664+1251T>C		intron_variant	Intron 6 of 25	ENST00000686413.1	NP_848512.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC9	ENST00000686413.1	c.664+1251T>C		intron_variant	Intron 6 of 25		NM_178425.4	ENSP00000509161.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15415 AN: 151984 Hom.: 1079 Cov.: 33

Gnomad AFR AF: 0.0715

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0747

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0876

Gnomad OTH AF: 0.0813

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

GnomAD4 genome AF: 0.102 AC: 15441 AN: 152100 Hom.: 1082 Cov.: 33 AF XY: 0.105 AC XY: 7795 AN XY: 74364

African (AFR) AF: 0.0718 AC: 2980 AN: 41526

American (AMR) AF: 0.188 AC: 2859 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3470

East Asian (EAS) AF: 0.331 AC: 1711 AN: 5172

South Asian (SAS) AF: 0.150 AC: 723 AN: 4820

European-Finnish (FIN) AF: 0.0747 AC: 793 AN: 10610

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0876 AC: 5953 AN: 67946

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0924 Hom.: 1284

Bravo AF: 0.109

Asia WGS AF: 0.213 AC: 739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.78
DANN	Benign	0.60
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs3814991; hg19: chr7-18634903; COSMIC: COSV67777025; COSMIC: COSV67777025;