17-44087517-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

The NM_005474.5(HDAC5):c.1779C>G(p.Asp593Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 1,610,846 control chromosomes in the GnomAD database, including 451,156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.71 (38798 hom., cov: 31)
  • Exomes 𝑓: 0.75 (412358 hom.)
• Consequence: HDAC5 NM_005474.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.837

Genes affected

HDAC5 (HGNC:14068): (histone deacetylase 5) 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 belongs to the class II histone deacetylase/acuc/apha family. It possesses histone deacetylase activity and represses transcription when tethered to a promoter. It coimmunoprecipitates only with HDAC3 family member and might form multicomplex proteins. It also interacts with myocyte enhancer factor-2 (MEF2) proteins, resulting in repression of MEF2-dependent genes. This gene is thought to be associated with colon cancer. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HDAC5
• BP4: Computational evidence support a benign effect (MetaRNN=8.665137E-7).
• BP6: Variant 17-44087517-G-C is Benign according to our data. Variant chr17-44087517-G-C is described in ClinVar as [Benign]. Clinvar id is 1300626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC5	NM_005474.5	c.1779C>G	p.Asp593Glu	missense_variant	13/27	ENST00000682912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC5	ENST00000682912.1	c.1779C>G	p.Asp593Glu	missense_variant	13/27		NM_005474.5	P4

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107715 AN: 151858 Hom.: 38766 Cov.: 31

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.717

Gnomad AMR AF: 0.767

Gnomad ASJ AF: 0.665

Gnomad EAS AF: 0.832

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.785

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.737

Gnomad OTH AF: 0.724

GnomAD3 exomes AF: 0.767 AC: 192349 AN: 250930 Hom.: 74431 AF XY: 0.770 AC XY: 104514 AN XY: 135670

Gnomad AFR exome AF: 0.588

Gnomad AMR exome AF: 0.840

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.835

Gnomad SAS exome AF: 0.865

Gnomad FIN exome AF: 0.776

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.750 AC: 1094459 AN: 1458872 Hom.: 412358 Cov.: 34 AF XY: 0.753 AC XY: 546780 AN XY: 725902

Gnomad4 AFR exome AF: 0.582

Gnomad4 AMR exome AF: 0.834

Gnomad4 ASJ exome AF: 0.661

Gnomad4 EAS exome AF: 0.838

Gnomad4 SAS exome AF: 0.861

Gnomad4 FIN exome AF: 0.778

Gnomad4 NFE exome AF: 0.742

Gnomad4 OTH exome AF: 0.738

GnomAD4 genome AF: 0.709 AC: 107796 AN: 151974 Hom.: 38798 Cov.: 31 AF XY: 0.717 AC XY: 53263 AN XY: 74278

Gnomad4 AFR AF: 0.590

Gnomad4 AMR AF: 0.767

Gnomad4 ASJ AF: 0.665

Gnomad4 EAS AF: 0.832

Gnomad4 SAS AF: 0.883

Gnomad4 FIN AF: 0.785

Gnomad4 NFE AF: 0.737

Gnomad4 OTH AF: 0.725

Alfa AF: 0.728 Hom.: 27845

Bravo AF: 0.699

TwinsUK AF: 0.741 AC: 2746

ALSPAC AF: 0.752 AC: 2897

ESP6500AA AF: 0.583 AC: 2569

ESP6500EA AF: 0.735 AC: 6317

ExAC AF: 0.761 AC: 92408

Asia WGS AF: 0.847 AC: 2940 AN: 3478

EpiCase AF: 0.743

EpiControl AF: 0.743

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.014
Dann	Benign	0.62
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.056	T;T;T
MetaRNN	Benign	8.7e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.070	N;N;.
REVEL	Benign	0.039
Sift	Benign	0.73	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.074
MutPred		0.22		.;Gain of solvent accessibility (P = 0.2601);Gain of solvent accessibility (P = 0.2601);
MPC		0.29
ClinPred		0.00077	T
GERP RS		1.4
Varity_R		0.033
gMVP		0.045

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: rs228757; hg19: chr17-42164885; COSMIC: COSV56816954; COSMIC: COSV56816954;