17-44078383-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_005474.5(HDAC5):c.3362C>T(p.Ala1121Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,370,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: HDAC5 NM_005474.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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]

G6PC3 (HGNC:24861): (glucose-6-phosphatase catalytic subunit 3) This gene encodes the catalytic subunit of glucose-6-phosphatase (G6Pase). G6Pase is located in the endoplasmic reticulum (ER) and catalyzes the hydrolysis of glucose-6-phosphate to glucose and phosphate in the last step of the gluconeogenic and glycogenolytic pathways. Mutations in this gene result in autosomal recessive severe congenital neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HDAC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.046499193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC5	NM_005474.5	c.3362C>T	p.Ala1121Val	missense_variant	27/27	ENST00000682912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC5	ENST00000682912.1	c.3362C>T	p.Ala1121Val	missense_variant	27/27		NM_005474.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000222 AC: 4 AN: 179798 Hom.: 0 AF XY: 0.0000314 AC XY: 3 AN XY: 95606

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000263 AC: 36 AN: 1370718 Hom.: 0 Cov.: 31 AF XY: 0.0000327 AC XY: 22 AN XY: 672798

Gnomad4 AFR exome AF: 0.0000330

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000318

Gnomad4 OTH exome AF: 0.0000177

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.3365C>T (p.A1122V) alteration is located in exon 27 (coding exon 26) of the HDAC5 gene. This alteration results from a C to T substitution at nucleotide position 3365, causing the alanine (A) at amino acid position 1122 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	15
Dann	Benign	0.95
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.95	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.94	N;N;.
REVEL	Benign	0.017
Sift	Benign	0.20	T;T;.
Sift4G	Benign	0.56	T;T;T
Polyphen		0.32	B;B;B
Vest4		0.042
MutPred		0.15		.;.;Loss of glycosylation at P1120 (P = 0.1356);
MVP		0.50
MPC		1.9
ClinPred		0.11	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.23

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: rs774870112; hg19: chr17-42155751;