17-44083611-A-C

Variant names:

• chr17-44083611-A-C
• rs1039360646
• NM_005474.5:c.2397T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005474.5(HDAC5):​c.2397T>G​(p.Ser799Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S799G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: HDAC5 NM_005474.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.123
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4202646).

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.2397T>G	p.Ser799Arg	missense	Exon 18 of 27	NP_005465.2	Q9UQL6-1
	HDAC5	NM_001015053.2		c.2400T>G	p.Ser800Arg	missense	Exon 18 of 27	NP_001015053.1	Q9UQL6-3
	HDAC5	NM_001382393.1		c.2397T>G	p.Ser799Arg	missense	Exon 18 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.2397T>G	p.Ser799Arg	missense	Exon 18 of 27	ENSP00000507606.1	Q9UQL6-1
	HDAC5	ENST00000586802.5	TSL:1	c.2397T>G	p.Ser799Arg	missense	Exon 18 of 27	ENSP00000468004.1	Q9UQL6-1
	HDAC5	ENST00000336057.9	TSL:1	c.2142T>G	p.Ser714Arg	missense	Exon 16 of 25	ENSP00000337290.4	Q9UQL6-2

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152254 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250848 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111980

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74382

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68044

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000848 Hom.: 0

Bravo AF: 0.0000982

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N
PhyloP100		-0.12
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.051	T
Polyphen		0.12	B
Vest4		0.63
MutPred		0.53		Gain of MoRF binding (P = 0.0654)
MVP		0.96
MPC		0.94
ClinPred		0.42	T
GERP RS		2.9
Varity_R		0.16
gMVP		0.92
Mutation Taster		=74/26	polymorphism

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: rs1039360646; hg19: chr17-42160979;