Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_006279.5(ST3GAL3):c.1079G>A(p.Arg360Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000349 in 1,614,142 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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. R360W) has been classified as Uncertain significance.
ST3GAL3 (HGNC:10866): (ST3 beta-galactoside alpha-2,3-sialyltransferase 3) The protein encoded by this gene is a type II membrane protein that catalyzes the transfer of sialic acid from CMP-sialic acid to galactose-containing substrates. The encoded protein is normally found in the Golgi apparatus but can be proteolytically processed to a soluble form. This protein is a member of glycosyltransferase family 29. Mutations in this gene have been associated with a form of autosomal recessive nonsymdromic cognitive disability as well as infantile epileptic encephalopathy. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]
Computational evidence support a benign effect (MetaRNN=0.0049929023).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000453 (69/152352) while in subpopulation SAS AF= 0.006 (29/4830). AF 95% confidence interval is 0.00429. There are 1 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jan 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Inborn genetic diseases Uncertain:1
Jul 10, 2017
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.R360Q variant (also known as c.1079G>A), located in coding exon 11 of the ST3GAL3 gene, results from a G to A substitution at nucleotide position 1079. The arginine at codon 360 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Intellectual disability, autosomal recessive 12;C3554316:Developmental and epileptic encephalopathy, 15 Uncertain:1
Mar 30, 2021
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
ST3GAL3 NM_174963.4 exon 13 p.Arg429Gln (c.1286G>A): This variant has not been reported in the literature but is present in 0.4% (135/30616) of South Asian alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-44395844-G-A). This variant is present in ClinVar (Variation ID:130377). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
ST3GAL3-related disorder Benign:1
Apr 06, 2022
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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). -
Early infantile epileptic encephalopathy with suppression bursts Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter