rs118203968
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_138387.4(G6PC3):c.758G>A(p.Arg253His) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,612,318 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253C) 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.758G>A | p.Arg253His | missense_variant | 6/6 | ENST00000269097.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
G6PC3 | ENST00000269097.9 | c.758G>A | p.Arg253His | missense_variant | 6/6 | 1 | NM_138387.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250074Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135388
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1460216Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 726550
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Autosomal recessive severe congenital neutropenia due to G6PC3 deficiency Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 253 of the G6PC3 protein (p.Arg253His). This variant is present in population databases (rs118203968, gnomAD 0.002%). This missense change has been observed in individuals with severe congenital neutropenia (PMID: 19118303, 20717171, 21385794). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1037). 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: 19118303). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | G6PC3: PM3:Very Strong, PM2, PP1, PS3:Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at