7-18727720-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_178425.4(HDAC9):c.1872A>G(p.Pro624=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,564,104 control chromosomes in the GnomAD database, including 58,789 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5571 hom., cov: 33)
  • Exomes 𝑓: 0.27 (53218 hom.)
• Consequence: HDAC9 NM_178425.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.28

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 7-18727720-A-G is Benign according to our data. Variant chr7-18727720-A-G is described in ClinVar as [Benign]. Clinvar id is 402927.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.518 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC9	NM_178425.4	c.1872A>G	p.Pro624=	synonymous_variant	13/26	ENST00000686413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC9	ENST00000686413.1	c.1872A>G	p.Pro624=	synonymous_variant	13/26		NM_178425.4	P4

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39631 AN: 151970 Hom.: 5564 Cov.: 33

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.268

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.260

GnomAD3 exomes AF: 0.293 AC: 59435 AN: 202658 Hom.: 9452 AF XY: 0.295 AC XY: 32778 AN XY: 111218

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.285

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.549

Gnomad SAS exome AF: 0.383

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.249

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.268 AC: 377882 AN: 1412014 Hom.: 53218 Cov.: 33 AF XY: 0.270 AC XY: 189604 AN XY: 701116

Gnomad4 AFR exome AF: 0.220

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.228

Gnomad4 EAS exome AF: 0.527

Gnomad4 SAS exome AF: 0.383

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.250

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.261 AC: 39668 AN: 152090 Hom.: 5571 Cov.: 33 AF XY: 0.267 AC XY: 19832 AN XY: 74344

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.535

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.247

Gnomad4 OTH AF: 0.259

Alfa AF: 0.249 Hom.: 6211

Bravo AF: 0.258

Asia WGS AF: 0.415 AC: 1441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	8.0
Dann	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs1178127; hg19: chr7-18767343; COSMIC: COSV67772674;