17-42901037-A-G

Position:

• chr17-42901037-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_000151.4(G6PC1):​c.161A>G​(p.Gln54Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q54P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: G6PC1 NM_000151.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.767

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-42901037-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.061810553).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
G6PC1	NM_000151.4	c.161A>G	p.Gln54Arg	missense_variant	1/5	ENST00000253801.7
G6PC1	NM_001270397.2	c.161A>G	p.Gln54Arg	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
G6PC1	ENST00000253801.7	c.161A>G	p.Gln54Arg	missense_variant	1/5	1	NM_000151.4	P1
G6PC1	ENST00000592383.5	c.161A>G	p.Gln54Arg	missense_variant	1/5	2
G6PC1	ENST00000585489.1	c.161A>G	p.Gln54Arg	missense_variant	1/4	5
G6PC1	ENST00000588481.1	n.226A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.3
DANN	Benign	0.59
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.062	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.76	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.23	T
Sift4G	Benign	0.69	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.084
MutPred		0.47		Loss of catalytic residue at Q54 (P = 0.039);Loss of catalytic residue at Q54 (P = 0.039);Loss of catalytic residue at Q54 (P = 0.039);
MVP		0.65
MPC		0.22
ClinPred		0.027	T
GERP RS		-0.74
Varity_R		0.060
gMVP		0.63

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: rs1057517008; hg19: chr17-41053054;