rs148559256
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_138387.4(G6PC3):c.829C>T(p.Gln277Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,459,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000010 ( 0 hom. )
Consequence
G6PC3
NM_138387.4 stop_gained
NM_138387.4 stop_gained
Scores
2
5
Clinical Significance
Conservation
PhyloP100: -0.605
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 17-44075831-C-T is Pathogenic according to our data. Variant chr17-44075831-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 189783.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
G6PC3 | NM_138387.4 | c.829C>T | p.Gln277Ter | stop_gained | 6/6 | ENST00000269097.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
G6PC3 | ENST00000269097.9 | c.829C>T | p.Gln277Ter | stop_gained | 6/6 | 1 | NM_138387.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249660Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135168
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1459470Hom.: 0 Cov.: 33 AF XY: 0.00000964 AC XY: 7AN XY: 726196
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Pathogenic:1Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | This sequence change creates a premature translational stop signal (p.Gln277*) in the G6PC3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acid(s) of the G6PC3 protein. This variant is present in population databases (rs148559256, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with autosomal recessive G6PC3 deficiency (PMID: 19118303, 23171239). ClinVar contains an entry for this variant (Variation ID: 189783). This variant disrupts a region of the G6PC3 protein in which other variant(s) (p.Leu325Arg) have been determined to be pathogenic (PMID: 24105461). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at