17-44070837-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138387.4(G6PC3):c.-129C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,062,146 control chromosomes in the GnomAD database, including 131,665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13668 hom., cov: 28)
  • Exomes 𝑓: 0.50 (117997 hom.)
• Consequence: G6PC3 NM_138387.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.02

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=-0.92).
• BP6: Variant 17-44070837-C-T is Benign according to our data. Variant chr17-44070837-C-T is described in ClinVar as [Benign]. Clinvar id is 323459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC3	NM_138387.4	c.-129C>T		5_prime_UTR_variant	1/6	ENST00000269097.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC3	ENST00000269097.9	c.-129C>T		5_prime_UTR_variant	1/6	1	NM_138387.4	P1

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57427 AN: 150486 Hom.: 13667 Cov.: 28

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.540

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.552

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.537

Gnomad OTH AF: 0.455

GnomAD3 exomes AF: 0.452 AC: 57757 AN: 127866 Hom.: 14239 AF XY: 0.469 AC XY: 32773 AN XY: 69896

Gnomad AFR exome AF: 0.0930

Gnomad AMR exome AF: 0.364

Gnomad ASJ exome AF: 0.513

Gnomad EAS exome AF: 0.206

Gnomad SAS exome AF: 0.549

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.542

Gnomad OTH exome AF: 0.498

GnomAD4 exome AF: 0.498 AC: 453524 AN: 911548 Hom.: 117997 Cov.: 12 AF XY: 0.503 AC XY: 234574 AN XY: 466576

Gnomad4 AFR exome AF: 0.0906

Gnomad4 AMR exome AF: 0.372

Gnomad4 ASJ exome AF: 0.506

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.422

Gnomad4 NFE exome AF: 0.534

Gnomad4 OTH exome AF: 0.470

GnomAD4 genome AF: 0.381 AC: 57420 AN: 150598 Hom.: 13668 Cov.: 28 AF XY: 0.377 AC XY: 27754 AN XY: 73578

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.386

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.537

Gnomad4 OTH AF: 0.457

Alfa AF: 0.385 Hom.: 1996

Bravo AF: 0.365

Asia WGS AF: 0.382 AC: 1328 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.92
Cadd	Benign	1.1
Dann	Benign	0.65

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: rs228758; hg19: chr17-42148205;