17-44070804-G-A

Position:

• chr17-44070804-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_138387.4(G6PC3):​c.-162G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 759,620 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0031 (8 hom.)
• Consequence: G6PC3 NM_138387.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.336

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00283 (431/152294) while in subpopulation NFE AF= 0.00368 (250/68004). AF 95% confidence interval is 0.0033. There are 1 homozygotes in gnomad4. There are 224 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC3	NM_138387.4	c.-162G>A		5_prime_UTR_variant	1/6	ENST00000269097.9	NP_612396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC3	ENST00000269097.9	c.-162G>A		5_prime_UTR_variant	1/6	1	NM_138387.4	ENSP00000269097	P1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 431 AN: 152176 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00820

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00368

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00259 AC: 307 AN: 118540 Hom.: 2 AF XY: 0.00278 AC XY: 179 AN XY: 64300

Gnomad AFR exome AF: 0.000491

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.00739

Gnomad EAS exome AF: 0.000676

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.00816

Gnomad NFE exome AF: 0.00319

Gnomad OTH exome AF: 0.00324

GnomAD4 exome AF: 0.00310 AC: 1883 AN: 607326 Hom.: 8 Cov.: 8 AF XY: 0.00314 AC XY: 1015 AN XY: 322734

Gnomad4 AFR exome AF: 0.000415

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.00624

Gnomad4 EAS exome AF: 0.000280

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.00863

Gnomad4 NFE exome AF: 0.00327

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152294 Hom.: 1 Cov.: 30 AF XY: 0.00301 AC XY: 224 AN XY: 74472

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.00820

Gnomad4 NFE AF: 0.00368

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00357 Hom.: 3

Bravo AF: 0.00183

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	7.6
DANN	Benign	0.78

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: rs536609615; hg19: chr17-42148172;