rs587777562
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_015599.3(PGM3):āc.737A>Gā(p.Asn246Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,472 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 Likely pathogenic (ā ā ).
Frequency
Consequence
NM_015599.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250886Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135592
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461472Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727044
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Immunodeficiency 23 Pathogenic:3
A Homozygous missense variation in exon 7 of the PGM3 gene that results in the amino acid substitution of Serine for Asparagine at codon 274 was detected. The observed variant c.821A>G (p.Asn274Ser) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by LRT, MutPred, PROVEAN and MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -
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segregates with the phenotype in an affected family -
Inborn genetic diseases Pathogenic:1
The c.821A>G (p.N274S) alteration is located in exon 7 (coding exon 6) of the PGM3 gene. This alteration results from an A to G substitution at nucleotide position 821, causing the asparagine (N) at amino acid position 274 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/250886) total alleles studied. The highest observed frequency was 0.005% (1/18382) of East Asian alleles. This alteration, also known as c.737A>G (p.Asn246Ser), was reported in multiple homozygous individuals with clinical features of PGM3-related immunodeficiency (Stray-Pedersen, 2014; Bernth-Jensen, 2016; NCBI ClinVar 2022)._x000D_ _x000D_ ClinVar citation: National Center for Biotechnology Information. ClinVar; [VCV000140732.3], https://www.ncbi.nlm.nih.gov/clinvar/variation/VCV000140732.3 (accessed May 11, 2023). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, N274S is deleterious. The variant disrupts the interaction of Asn274 with metal-binding loop and active serine loop (Stray-Pedersen, 2014; Raimi, 2018). In vitro expression studies in E. coli demonstrated that this substitution abolished PGM3 function with residual function of approximately 1% compared to wild type (Stray-Pedersen, 2014). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Severe combined immunodeficiency disease Pathogenic:1
Variant summary: PGM3 c.821A>G (p.Asn274Ser) results in a conservative amino acid change located in the Phosphoacetylglucosamine mutase AMG1, domain II (IPR049023) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250886 control chromosomes. c.821A>G (also known as c.737A>G , p.Asn246Ser) has been reported in the literature in individuals affected with PGM3-related immunodeficiency (examples: Stray-Pedersen_2014 and Bernth-Jensen_2016). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity ( Stray-Pedersen_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24931394, 26409661). ClinVar contains an entry for this variant (Variation ID: 140732). Based on the evidence outlined above, the variant was classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at