17-44080885-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005474.5(HDAC5):c.2608-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0061 in 1,614,068 control chromosomes in the GnomAD database, including 513 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (269 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (244 hom.)
• Consequence: HDAC5 NM_005474.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002254
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.153

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-44080885-A-G is Benign according to our data. Variant chr17-44080885-A-G is described in ClinVar as [Benign]. Clinvar id is 771030.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC5	NM_005474.5	c.2608-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000682912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC5	ENST00000682912.1	c.2608-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_005474.5	P4

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4801 AN: 152114 Hom.: 269 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000721

Gnomad OTH AF: 0.0215

GnomAD3 exomes AF: 0.00795 AC: 2000 AN: 251426 Hom.: 88 AF XY: 0.00567 AC XY: 770 AN XY: 135878

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00345 AC: 5045 AN: 1461836 Hom.: 244 Cov.: 34 AF XY: 0.00297 AC XY: 2161 AN XY: 727232

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.00559

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000406

Gnomad4 OTH exome AF: 0.00667

GnomAD4 genome AF: 0.0316 AC: 4808 AN: 152232 Hom.: 269 Cov.: 32 AF XY: 0.0308 AC XY: 2290 AN XY: 74446

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000721

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0199 Hom.: 62

Bravo AF: 0.0362

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

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 13, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.1
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00023
dbscSNV1_RF	Benign	0.0080
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: rs8064428; hg19: chr17-42158253;