rs8064428

Variant names:

• chr17-44080885-A-G
• rs8064428
• NM_005474.5:c.2608-3T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005474.5(HDAC5):​c.2608-3T>C variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0002254
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.153
• Publications: 1 publications found

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]

G6PC3 Gene-Disease associations (from GenCC):

• autosomal recessive severe congenital neutropenia due to G6PC3 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 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 VariationId is 771030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005474.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC5	NM_005474.5	MANE Select	c.2608-3T>C		splice_region intron	N/A	NP_005465.2	Q9UQL6-1
	HDAC5	NM_001015053.2		c.2611-3T>C		splice_region intron	N/A	NP_001015053.1	Q9UQL6-3
	HDAC5	NM_001382393.1		c.2608-3T>C		splice_region intron	N/A	NP_001369322.1	Q9UQL6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDAC5	ENST00000682912.1	MANE Select	c.2608-3T>C		splice_region intron	N/A	ENSP00000507606.1	Q9UQL6-1
	HDAC5	ENST00000586802.5	TSL:1	c.2608-3T>C		splice_region intron	N/A	ENSP00000468004.1	Q9UQL6-1
	HDAC5	ENST00000336057.9	TSL:1	c.2353-3T>C		splice_region intron	N/A	ENSP00000337290.4	Q9UQL6-2

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

GnomAD2 exomes AF: 0.00795 AC: 2000 AN: 251426 AF XY: 0.00567

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 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

African (AFR) AF: 0.116 AC: 3875 AN: 33476

American (AMR) AF: 0.00559 AC: 250 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53408

Middle Eastern (MID) AF: 0.00641 AC: 37 AN: 5768

European-Non Finnish (NFE) AF: 0.000406 AC: 451 AN: 1111986

Other (OTH) AF: 0.00667 AC: 403 AN: 60392

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

African (AFR) AF: 0.110 AC: 4563 AN: 41516

American (AMR) AF: 0.00961 AC: 147 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000721 AC: 49 AN: 67996

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.0204 Hom.: 96

Bravo AF: 0.0362

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.1
DANN	Benign	0.66
PhyloP100		-0.15
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8064428; hg19: chr17-42158253;