rs228757

Variant names:

• chr17-44087517-G-C
• rs228757
• NM_005474.5:c.1779C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-44087517-G-C
• chr17-44087517-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 14/21 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.837
• Publications: 47 publications found

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]

HDAC5 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 1300626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.861 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005474.5. 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
	HDAC5	NM_005474.5	MANE Select	c.1779C>G	p.Asp593Glu	missense	Exon 13 of 27	NP_005465.2	Q9UQL6-1
	HDAC5	NM_001015053.2		c.1782C>G	p.Asp594Glu	missense	Exon 13 of 27	NP_001015053.1	Q9UQL6-3
	HDAC5	NM_001382393.1		c.1779C>G	p.Asp593Glu	missense	Exon 13 of 27	NP_001369322.1	Q9UQL6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC5	ENST00000682912.1	MANE Select	c.1779C>G	p.Asp593Glu	missense	Exon 13 of 27	ENSP00000507606.1	Q9UQL6-1
	HDAC5	ENST00000586802.5	TSL:1	c.1779C>G	p.Asp593Glu	missense	Exon 13 of 27	ENSP00000468004.1	Q9UQL6-1
	HDAC5	ENST00000336057.9	TSL:1	c.1779C>G	p.Asp593Glu	missense	Exon 13 of 25	ENSP00000337290.4	Q9UQL6-2

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

GnomAD2 exomes AF: 0.767 AC: 192349 AN: 250930 AF XY: 0.770

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 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

African (AFR) AF: 0.582 AC: 19444 AN: 33406

American (AMR) AF: 0.834 AC: 37301 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 17268 AN: 26108

East Asian (EAS) AF: 0.838 AC: 33281 AN: 39694

South Asian (SAS) AF: 0.861 AC: 74191 AN: 86206

European-Finnish (FIN) AF: 0.778 AC: 41514 AN: 53386

Middle Eastern (MID) AF: 0.724 AC: 4172 AN: 5760

European-Non Finnish (NFE) AF: 0.742 AC: 822791 AN: 1109322

Other (OTH) AF: 0.738 AC: 44497 AN: 60290

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

African (AFR) AF: 0.590 AC: 24438 AN: 41424

American (AMR) AF: 0.767 AC: 11717 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 2307 AN: 3468

East Asian (EAS) AF: 0.832 AC: 4287 AN: 5152

South Asian (SAS) AF: 0.883 AC: 4253 AN: 4816

European-Finnish (FIN) AF: 0.785 AC: 8308 AN: 10588

Middle Eastern (MID) AF: 0.716 AC: 209 AN: 292

European-Non Finnish (NFE) AF: 0.737 AC: 50097 AN: 67948

Other (OTH) AF: 0.725 AC: 1526 AN: 2106

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.056	T
MetaRNN	Benign	8.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.48	N
PhyloP100		-0.84
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.039
Sift	Benign	0.73	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.22		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
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: rs228757; hg19: chr17-42164885; COSMIC: COSV56816954; COSMIC: COSV56816954;