rs367816430

Variant names:

• chr17-42900832-G-A
• rs367816430
• NM_000151.4:c.-45G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000151.4(G6PC1):​c.-45G>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 0.00156 in 1,522,154 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (6 hom.)
• Consequence: G6PC1 NM_000151.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.203
• Publications: 0 publications found

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]

G6PC1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to glucose-6-phosphatase deficiency type IA

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• glycogen storage disease I

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-42900832-G-A is Benign according to our data. Variant chr17-42900832-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137405.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000151.4. 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
	G6PC1	NM_000151.4	MANE Select	c.-45G>A		5_prime_UTR	Exon 1 of 5	NP_000142.2	P35575-1
	G6PC1	NM_001270397.2		c.-45G>A		5_prime_UTR	Exon 1 of 5	NP_001257326.1	P35575-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	G6PC1	ENST00000253801.7	TSL:1 MANE Select	c.-45G>A		5_prime_UTR	Exon 1 of 5	ENSP00000253801.1	P35575-1
	G6PC1	ENST00000887113.1		c.-45G>A		5_prime_UTR	Exon 1 of 5	ENSP00000557172.1
	G6PC1	ENST00000887112.1		c.-45G>A		5_prime_UTR	Exon 1 of 5	ENSP00000557171.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00116 AC: 281 AN: 242130 AF XY: 0.00131

Gnomad AFR exome AF: 0.000322

Gnomad AMR exome AF: 0.000509

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000522

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00158 AC: 2162 AN: 1369830 Hom.: 6 Cov.: 21 AF XY: 0.00161 AC XY: 1106 AN XY: 686094

African (AFR) AF: 0.000348 AC: 11 AN: 31622

American (AMR) AF: 0.000620 AC: 27 AN: 43580

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25472

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39162

South Asian (SAS) AF: 0.000646 AC: 54 AN: 83608

European-Finnish (FIN) AF: 0.000640 AC: 34 AN: 53154

Middle Eastern (MID) AF: 0.00338 AC: 19 AN: 5620

European-Non Finnish (NFE) AF: 0.00187 AC: 1922 AN: 1030360

Other (OTH) AF: 0.00162 AC: 93 AN: 57252

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152324 Hom.: 0 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74472

African (AFR) AF: 0.000361 AC: 15 AN: 41572

American (AMR) AF: 0.00131 AC: 20 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00132

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Glycogen storage disease due to glucose-6-phosphatase deficiency type IA (2)
-	-	1	G6PC1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.8
DANN	Benign	0.61
PhyloP100		0.20
PromoterAI		-0.023	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs367816430; hg19: chr17-41052849;