rs113416399

chr17-44076045-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_138387.4(G6PC3):c.*2T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,612,470 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (90 hom.)
• Consequence: G6PC3 NM_138387.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.440

Genes affected

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-44076045-T-C is Benign according to our data. Variant chr17-44076045-T-C is described in ClinVar as [Benign]. Clinvar id is 211056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00691 (1052/152312) while in subpopulation NFE AF= 0.0127 (863/68022). AF 95% confidence interval is 0.012. There are 4 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC3	NM_138387.4	c.*2T>C		3_prime_UTR_variant	6/6	ENST00000269097.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC3	ENST00000269097.9	c.*2T>C		3_prime_UTR_variant	6/6	1	NM_138387.4	P1

Frequencies

GnomAD3 genomes AF: 0.00691 AC: 1052 AN: 152194 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00643 AC: 1611 AN: 250448 Hom.: 8 AF XY: 0.00630 AC XY: 853 AN XY: 135474

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00286

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00179

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.00848

GnomAD4 exome AF: 0.0106 AC: 15485 AN: 1460158 Hom.: 90 Cov.: 33 AF XY: 0.0105 AC XY: 7613 AN XY: 726528

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00304

Gnomad4 ASJ exome AF: 0.000689

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00250

Gnomad4 FIN exome AF: 0.00234

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.00924

GnomAD4 genome AF: 0.00691 AC: 1052 AN: 152312 Hom.: 4 Cov.: 32 AF XY: 0.00615 AC XY: 458 AN XY: 74482

Gnomad4 AFR AF: 0.00229

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00956 Hom.: 4

Bravo AF: 0.00703

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0112

EpiControl AF: 0.00948

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 19, 2016

- -

G6PC3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 16, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

G6PC3: BS1, BS2 -

Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	2.0
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs113416399; hg19: chr17-42153413;