15-74897636-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_002435.3(MPI):c.1178G>C(p.Gly393Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,614,212 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 Uncertain significance (★★).
Frequency
Consequence
NM_002435.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000187 AC: 47AN: 251494Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135922
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461890Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20AN XY: 727246
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74482
ClinVar
Submissions by phenotype
MPI-congenital disorder of glycosylation Uncertain:4
This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 393 of the MPI protein (p.Gly393Ala). This variant is present in population databases (rs201815588, gnomAD 0.1%). This missense change has been observed in individual(s) with congenital disorder of glycosylation type 1b (PMID: 32905087). ClinVar contains an entry for this variant (Variation ID: 317143). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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not provided Uncertain:1
Observed with a second MPI variant but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes; this individual is reported with teenage-onset cerebral venous sinus thrombosis as the first and only presenting symptom followed by absent mannose phosphate isomerase activity in leukocytes (Mhlhausen C et al., 2020); 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: 32905087) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at