chr16-1351972-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM2PM5BP4_ModerateBS1_Supporting
The NM_032520.5(GNPTG):c.7G>A(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,317,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3V) has been classified as Likely pathogenic.
Frequency
Consequence
NM_032520.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000488 AC: 74AN: 151670Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000566 AC: 66AN: 1165384Hom.: 0 Cov.: 32 AF XY: 0.0000603 AC XY: 34AN XY: 564232
GnomAD4 genome AF: 0.000494 AC: 75AN: 151778Hom.: 0 Cov.: 32 AF XY: 0.000512 AC XY: 38AN XY: 74196
ClinVar
Submissions by phenotype
GNPTG-mucolipidosis Uncertain:3
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not provided Uncertain:2
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3 of the GNPTG protein (p.Ala3Thr). This variant is present in population databases (no rsID available, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with GNPTG-related conditions. ClinVar contains an entry for this variant (Variation ID: 550565). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -
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not specified Benign:1
Variant summary: GNPTG c.7G>A (p.Ala3Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 1317162 control chromosomes, predominantly at a frequency of 0.0019 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.075 fold of the estimated maximal expected allele frequency for a pathogenic variant in GNPTG causing Mucolipidosis III Gamma phenotype (0.0018). To our knowledge, no occurrence of c.7G>A in individuals affected with Mucolipidosis III Gamma and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 550565). Based on the evidence outlined above, the variant was classified as likely benign. -
GNPTG-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at