chr17-42900800-G-A

Position:

• chr17-42900800-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000151.4(G6PC1):​c.-77G>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 0.0115 in 1,192,660 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0090 (7 hom., cov: 32)
  • Exomes 𝑓: 0.012 (98 hom.)
• Consequence: G6PC1 NM_000151.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.49

Genes affected

G6PC1 (HGNC:4056): (glucose-6-phosphatase catalytic subunit 1) Glucose-6-phosphatase (G6Pase) is a multi-subunit integral membrane protein of the endoplasmic reticulum that is composed of a catalytic subunit and transporters for G6P, inorganic phosphate, and glucose. This gene (G6PC) is one of the three glucose-6-phosphatase catalytic-subunit-encoding genes in human: G6PC, G6PC2 and G6PC3. Glucose-6-phosphatase catalyzes the hydrolysis of D-glucose 6-phosphate to D-glucose and orthophosphate and is a key enzyme in glucose homeostasis, functioning in gluconeogenesis and glycogenolysis. Mutations in this gene cause glycogen storage disease type I (GSD1). This disease, also known as von Gierke disease, is a metabolic disorder characterized by severe hypoglycemia associated with the accumulation of glycogen and fat in the liver and kidneys.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 17-42900800-G-A is Benign according to our data. Variant chr17-42900800-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 889444.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 = 0.00899 (1369/152308) while in subpopulation NFE AF= 0.0135 (920/68022). AF 95% confidence interval is 0.0128. There are 7 homozygotes in gnomad4. There are 615 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
G6PC1	NM_000151.4	c.-77G>A		5_prime_UTR_variant	1/5	ENST00000253801.7	NP_000142.2
G6PC1	NM_001270397.2	c.-77G>A		5_prime_UTR_variant	1/5		NP_001257326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
G6PC1	ENST00000253801	c.-77G>A		5_prime_UTR_variant	1/5	1	NM_000151.4	ENSP00000253801.1
G6PC1	ENST00000592383	c.-77G>A		5_prime_UTR_variant	1/5	2		ENSP00000465958.1
G6PC1	ENST00000585489	c.-77G>A		5_prime_UTR_variant	1/4	5		ENSP00000466202.1
G6PC1	ENST00000588481.1	n.-12G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1370 AN: 152190 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.0119 AC: 12336 AN: 1040352 Hom.: 98 Cov.: 14 AF XY: 0.0118 AC XY: 6287 AN XY: 532516

Gnomad4 AFR exome AF: 0.00190

Gnomad4 AMR exome AF: 0.00484

Gnomad4 ASJ exome AF: 0.0231

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.00542

Gnomad4 FIN exome AF: 0.00425

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.00899 AC: 1369 AN: 152308 Hom.: 7 Cov.: 32 AF XY: 0.00826 AC XY: 615 AN XY: 74464

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.00798

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.0135

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00999 Hom.: 1

Bravo AF: 0.00952

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	G6PC1: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2021	This variant is associated with the following publications: (PMID: 15918042) -

Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

G6PC1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.95

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: rs145752565; hg19: chr17-41052817;