7-18647919-A-T

Variant names:

• chr7-18647919-A-T
• rs35614472
• NM_178425.4:c.1170A>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_178425.4(HDAC9):​c.1170A>T​(p.Pro390Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,612,834 control chromosomes in the GnomAD database, including 209 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (25 hom., cov: 33)
  • Exomes 𝑓: 0.012 (184 hom.)
• Consequence: HDAC9 NM_178425.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0890
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-18647919-A-T is Benign according to our data. Variant chr7-18647919-A-T is described in ClinVar as Benign. ClinVar VariationId is 402926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.089 with no splicing effect.
• BS2: High AC in GnomAd4 at 1716 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDAC9	NM_178425.4	c.1170A>T	p.Pro390Pro	synonymous_variant	Exon 10 of 26	ENST00000686413.1	NP_848512.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDAC9	ENST00000686413.1	c.1170A>T	p.Pro390Pro	synonymous_variant	Exon 10 of 26		NM_178425.4	ENSP00000509161.1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1718 AN: 152180 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0115

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0119 AC: 2932 AN: 246840 AF XY: 0.0119

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.0000565

Gnomad FIN exome AF: 0.0516

Gnomad NFE exome AF: 0.0120

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0121 AC: 17728 AN: 1460536 Hom.: 184 Cov.: 31 AF XY: 0.0119 AC XY: 8619 AN XY: 726498

African (AFR) AF: 0.00200 AC: 67 AN: 33448

American (AMR) AF: 0.00442 AC: 197 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 471 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00228 AC: 196 AN: 86132

European-Finnish (FIN) AF: 0.0494 AC: 2636 AN: 53310

Middle Eastern (MID) AF: 0.00972 AC: 56 AN: 5762

European-Non Finnish (NFE) AF: 0.0121 AC: 13468 AN: 1111398

Other (OTH) AF: 0.0106 AC: 637 AN: 60316

GnomAD4 genome AF: 0.0113 AC: 1716 AN: 152298 Hom.: 25 Cov.: 33 AF XY: 0.0131 AC XY: 973 AN XY: 74468

African (AFR) AF: 0.00231 AC: 96 AN: 41578

American (AMR) AF: 0.00680 AC: 104 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0605 AC: 642 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0115 AC: 779 AN: 68024

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0112 Hom.: 7

Bravo AF: 0.00733

Asia WGS AF: 0.000577 AC: 2 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	-0.82
CADD	Benign	6.4
DANN	Benign	0.44
PhyloP100		-0.089
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: rs35614472; hg19: chr7-18687542;