17-44078524-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_005474.5(HDAC5):c.3305C>T(p.Ala1102Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,610,580 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (7 hom.)
• Consequence: HDAC5 NM_005474.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.19

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 -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HDAC5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036851466).
• BP6: Variant 17-44078524-G-A is Benign according to our data. Variant chr17-44078524-G-A is described in ClinVar as [Benign]. Clinvar id is 784744.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0027 (411/152268) while in subpopulation AMR AF= 0.0226 (346/15300). AF 95% confidence interval is 0.0207. There are 6 homozygotes in gnomad4. There are 254 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 410 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC5	NM_005474.5	c.3305C>T	p.Ala1102Val	missense_variant	26/27	ENST00000682912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC5	ENST00000682912.1	c.3305C>T	p.Ala1102Val	missense_variant	26/27		NM_005474.5	P4

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152152 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00284 AC: 699 AN: 245994 Hom.: 8 AF XY: 0.00225 AC XY: 300 AN XY: 133360

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.0177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00242

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000451

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.000670 AC: 977 AN: 1458312 Hom.: 7 Cov.: 32 AF XY: 0.000597 AC XY: 433 AN XY: 725404

Gnomad4 AFR exome AF: 0.00132

Gnomad4 AMR exome AF: 0.0161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00146

Gnomad4 SAS exome AF: 0.000709

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00121

GnomAD4 genome AF: 0.00270 AC: 411 AN: 152268 Hom.: 6 Cov.: 32 AF XY: 0.00341 AC XY: 254 AN XY: 74448

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.0226

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00290

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000296 Hom.: 0

Bravo AF: 0.00325

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00190 AC: 230

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

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 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Benign	0.95
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.20	N;N;.
REVEL	Benign	0.025
Sift	Benign	0.41	T;T;.
Sift4G	Benign	0.26	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.28
MVP		0.32
MPC		0.95
ClinPred		0.0050	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.024
gMVP		0.28

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: rs138005262; hg19: chr17-42155892;