7-18727720-A-G

Variant names:

• chr7-18727720-A-G
• rs1178127
• NM_178425.4:c.1872A>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_178425.4(HDAC9):​c.1872A>G​(p.Pro624Pro) 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
• Publications: 25 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 -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 VariationId 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 rank	MANE	Protein	UniProt
HDAC9	NM_178425.4	c.1872A>G	p.Pro624Pro	synonymous_variant	Exon 13 of 26	ENST00000686413.1	NP_848512.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC9	ENST00000686413.1	c.1872A>G	p.Pro624Pro	synonymous_variant	Exon 13 of 26		NM_178425.4	ENSP00000509161.1

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

GnomAD2 exomes AF: 0.293 AC: 59435 AN: 202658 AF XY: 0.295

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 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

African (AFR) AF: 0.220 AC: 6656 AN: 30264

American (AMR) AF: 0.280 AC: 9132 AN: 32630

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5511 AN: 24190

East Asian (EAS) AF: 0.527 AC: 19445 AN: 36918

South Asian (SAS) AF: 0.383 AC: 29840 AN: 77974

European-Finnish (FIN) AF: 0.306 AC: 16170 AN: 52778

Middle Eastern (MID) AF: 0.291 AC: 1627 AN: 5598

European-Non Finnish (NFE) AF: 0.250 AC: 273351 AN: 1093390

Other (OTH) AF: 0.277 AC: 16150 AN: 58272

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

African (AFR) AF: 0.218 AC: 9060 AN: 41518

American (AMR) AF: 0.268 AC: 4101 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 765 AN: 3466

East Asian (EAS) AF: 0.535 AC: 2758 AN: 5154

South Asian (SAS) AF: 0.398 AC: 1919 AN: 4820

European-Finnish (FIN) AF: 0.305 AC: 3221 AN: 10560

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16777 AN: 67970

Other (OTH) AF: 0.259 AC: 548 AN: 2116

Alfa AF: 0.251 Hom.: 9393

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

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		2.3
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: rs1178127; hg19: chr7-18767343; COSMIC: COSV67772674;