7-18496317-C-G

Variant names:

• chr7-18496317-C-G
• rs199565230
• NM_178425.4:c.15C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001321896.2(HDAC9):​c.-138C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,612,878 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: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: HDAC9 NM_001321896.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.22
• Publications: 5 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18883336).
• BS2: High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321896.2. 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.15C>G	p.Ile5Met	missense	Exon 2 of 26	NP_848512.1	Q9UKV0-7
	HDAC9	NM_001321896.2		c.-138C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001308825.1	Q9UKV0-10
	HDAC9	NM_001321887.2		c.-138C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 13	NP_001308816.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC9	ENST00000686413.1	MANE Select	c.15C>G	p.Ile5Met	missense	Exon 2 of 26	ENSP00000509161.1	Q9UKV0-7
	HDAC9	ENST00000441542.7	TSL:1	c.15C>G	p.Ile5Met	missense	Exon 1 of 25	ENSP00000408617.2	Q9UKV0-7
	HDAC9	ENST00000406451.8	TSL:1	c.15C>G	p.Ile5Met	missense	Exon 2 of 26	ENSP00000384657.3	Q9UKV0-5

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000282 AC: 7 AN: 248654 AF XY: 0.0000297

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: 0.0000533

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 197 AN: 1460820 Hom.: 0 Cov.: 30 AF XY: 0.000125 AC XY: 91 AN XY: 726714

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000174 AC: 193 AN: 1111312

Other (OTH) AF: 0.0000663 AC: 4 AN: 60320

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000496 AC: 6

EpiCase AF: 0.0000546

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

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	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Benign	0.93
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.55	N
PhyloP100		7.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.12
Sift	Benign	0.097	T
Sift4G	Benign	0.25	T
Polyphen		0.80	P
Vest4		0.43
MVP		0.22
MPC		0.52
ClinPred		0.12	T
GERP RS		6.2
PromoterAI		-0.021	Neutral
Varity_R		0.19
gMVP		0.13
Mutation Taster		=90/10	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: rs199565230; hg19: chr7-18535940;