17-44080836-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_005474.5(HDAC5):c.2654C>A(p.Pro885His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 1,614,172 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P885S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (11 hom.)
• Consequence: HDAC5 NM_005474.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 10.0

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HDAC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.015381098).
• BP6: Variant 17-44080836-G-T is Benign according to our data. Variant chr17-44080836-G-T is described in ClinVar as [Benign]. Clinvar id is 718759.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 381 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC5	NM_005474.5	c.2654C>A	p.Pro885His	missense_variant	21/27	ENST00000682912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC5	ENST00000682912.1	c.2654C>A	p.Pro885His	missense_variant	21/27		NM_005474.5	P4

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 381 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00745

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00329

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00245 AC: 617 AN: 251478 Hom.: 2 AF XY: 0.00249 AC XY: 338 AN XY: 135916

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00878

Gnomad NFE exome AF: 0.00250

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00244 AC: 3574 AN: 1461858 Hom.: 11 Cov.: 33 AF XY: 0.00244 AC XY: 1773 AN XY: 727234

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00593

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000614

Gnomad4 FIN exome AF: 0.00835

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.00250 AC: 381 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.00267 AC XY: 199 AN XY: 74462

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00745

Gnomad4 NFE AF: 0.00329

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00157

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00213

EpiControl AF: 0.00273

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

Invitae

Jul 17, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Uncertain	0.61	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-7.0	D;D;.
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.79
MVP		0.79
MPC		2.1
ClinPred		0.14	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs139312109; hg19: chr17-42158204;