chr17-44075780-G-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_138387.4(G6PC3):āc.778G>Cā(p.Gly260Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000114 in 1,612,074 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 (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G260D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_138387.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
G6PC3 | NM_138387.4 | c.778G>C | p.Gly260Arg | missense_variant | 6/6 | ENST00000269097.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
G6PC3 | ENST00000269097.9 | c.778G>C | p.Gly260Arg | missense_variant | 6/6 | 1 | NM_138387.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000560 AC: 14AN: 249872Hom.: 0 AF XY: 0.0000370 AC XY: 5AN XY: 135272
GnomAD4 exome AF: 0.000120 AC: 175AN: 1459920Hom.: 0 Cov.: 33 AF XY: 0.000128 AC XY: 93AN XY: 726390
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74318
ClinVar
Submissions by phenotype
Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the G6PC3 protein (p.Gly260Arg). This variant is present in population databases (rs200478425, gnomAD 0.01%). This missense change has been observed in individuals with syndromic severe congenital neutropenia (PMID: 19118303, 20616219, 23180359, 23441086). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30874). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt G6PC3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects G6PC3 function (PMID: 25492228). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 14, 2010 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 18, 2023 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 03, 2023 | PP1, PP3, PM3_very_strong, PS3_moderate, PS4 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 2022 | Reported as a common pathogenic variant among individuals of European background (Banka and Newman, 2013); Published functional studies demonstrate a damaging effect with no detectable enzyme activity (Lin et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23441086, 19118303, 19775295, 20220065, 20616219, 23180359, 25491320, 23758768, 25492228) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at