17-44078674-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005474.5(HDAC5):c.3164-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,604,644 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (9 hom.)
• Consequence: HDAC5 NM_005474.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003272
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.155

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-44078674-G-A is Benign according to our data. Variant chr17-44078674-G-A is described in ClinVar as [Benign]. Clinvar id is 774724.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 190 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDAC5	NM_005474.5	c.3164-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000682912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDAC5	ENST00000682912.1	c.3164-9C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_005474.5	P4

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152188 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00179

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00173 AC: 425 AN: 245636 Hom.: 4 AF XY: 0.00210 AC XY: 280 AN XY: 133048

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00539

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.00167 AC: 2423 AN: 1452338 Hom.: 9 Cov.: 32 AF XY: 0.00185 AC XY: 1333 AN XY: 722100

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000964

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00589

Gnomad4 FIN exome AF: 0.00120

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00188

GnomAD4 genome AF: 0.00125 AC: 191 AN: 152306 Hom.: 2 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74472

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00663

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00179

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00110

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Jun 08, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.9
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
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: rs189029714; hg19: chr17-42156042;