rs756682220
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_021971.4(GMPPB):c.877C>T(p.Arg293Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000625 in 1,600,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R293P) has been classified as Uncertain significance.
Frequency
Consequence
NM_021971.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GMPPB | NM_021971.4 | c.877C>T | p.Arg293Trp | missense_variant | 8/9 | ENST00000308388.7 | |
GMPPB | NM_013334.4 | c.877C>T | p.Arg293Trp | missense_variant | 8/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GMPPB | ENST00000308388.7 | c.877C>T | p.Arg293Trp | missense_variant | 8/9 | 1 | NM_021971.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000666 AC: 1AN: 150168Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250138Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135428
GnomAD4 exome AF: 0.00000621 AC: 9AN: 1449940Hom.: 0 Cov.: 43 AF XY: 0.00000555 AC XY: 4AN XY: 721270
GnomAD4 genome ? AF: 0.00000666 AC: 1AN: 150168Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 73328
ClinVar
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14;C3809221:Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14;C4518000:Autosomal recessive limb-girdle muscular dystrophy type 2T Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 16, 2017 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with GMPPB-related disease. This variant is present in population databases (rs756682220, ExAC 0.01%). This sequence change replaces arginine with tryptophan at codon 293 of the GMPPB protein (p.Arg293Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 31, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31211170, 30684953, 28433477) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at