NM_178425.4:c.3088T>A

Variant names:

• chr7-18975871-T-A
• rs1554416862
• NM_178425.4:c.3088T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178425.4(HDAC9):​c.3088T>A​(p.Leu1030Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1030V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HDAC9 NM_178425.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.881
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.110114336).

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.3088T>A	p.Leu1030Met	missense	Exon 25 of 26	NP_848512.1	Q9UKV0-7
	HDAC9	NM_178423.3		c.3079T>A	p.Leu1027Met	missense	Exon 25 of 26	NP_848510.1	Q9UKV0-5
	HDAC9	NM_001321868.2		c.3013T>A	p.Leu1005Met	missense	Exon 25 of 26	NP_001308797.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC9	ENST00000686413.1	MANE Select	c.3088T>A	p.Leu1030Met	missense	Exon 25 of 26	ENSP00000509161.1	Q9UKV0-7
	HDAC9	ENST00000441542.7	TSL:1	c.3088T>A	p.Leu1030Met	missense	Exon 24 of 25	ENSP00000408617.2	Q9UKV0-7
	HDAC9	ENST00000406451.8	TSL:1	c.3079T>A	p.Leu1027Met	missense	Exon 25 of 26	ENSP00000384657.3	Q9UKV0-5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Uncertain	0.98
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.86	T
PhyloP100		-0.88
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.28	N
REVEL	Benign	0.10
Sift	Benign	0.085	T
Sift4G	Benign	0.10	T
Polyphen		0.79	P
Vest4		0.40
MutPred		0.27		Loss of loop (P = 0.0603)
MVP		0.37
MPC		0.34
ClinPred		0.18	T
GERP RS		-9.0
gMVP		0.13
Mutation Taster		=94/6	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: rs1554416862; hg19: chr7-19015494;