rs121434532
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The NM_000262.3(NAGA):c.479C>G(p.Ser160Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000676 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S160S) has been classified as Likely benign.
Frequency
Consequence
NM_000262.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NAGA | NM_000262.3 | c.479C>G | p.Ser160Cys | missense_variant | 4/9 | ENST00000396398.8 | |
NAGA | NM_001362848.1 | c.479C>G | p.Ser160Cys | missense_variant | 5/10 | ||
NAGA | NM_001362850.1 | c.479C>G | p.Ser160Cys | missense_variant | 5/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NAGA | ENST00000396398.8 | c.479C>G | p.Ser160Cys | missense_variant | 4/9 | 1 | NM_000262.3 | P1 | |
NAGA | ENST00000402937.1 | c.479C>G | p.Ser160Cys | missense_variant | 5/10 | 5 | P1 | ||
NAGA | ENST00000403363.5 | c.479C>G | p.Ser160Cys | missense_variant | 5/10 | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000480 AC: 73AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000744 AC: 187AN: 251336Hom.: 0 AF XY: 0.000685 AC XY: 93AN XY: 135852
GnomAD4 exome AF: 0.000696 AC: 1018AN: 1461856Hom.: 1 Cov.: 33 AF XY: 0.000664 AC XY: 483AN XY: 727234
GnomAD4 genome ? AF: 0.000479 AC: 73AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31AN XY: 74444
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 19, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 25, 2018 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 19683538, 27138754, 23045655, 8782044, 11313741, 31980526, 31589614) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 27, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2017 | - - |
Alpha-N-acetylgalactosaminidase deficiency type 1 Pathogenic:1Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 26, 2013 | The Ser160Cys variant in NAGA has been previously identified in 1 compound heterozygous individual with Alpha-N-acetylgalactosaminidase (NAGA) deficiency and segregated with enzyme deficiency in a sibling (Keulemans 1996). Functional studies indicate this variant results in 4% residual NAGA activity possibly explaining the milder than typical phenotype, particularly in the clinically unaffected sibling with reduced enzyme activity (Keulemans 1996). In summary, this variant is likely pathogenic, though additional studies are required to fully establish its clinical significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 160 of the NAGA protein (p.Ser160Cys). This variant is present in population databases (rs121434532, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-NAGA deficiency (PMID: 8782044). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 18165). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NAGA protein function. Experimental studies have shown that this missense change affects NAGA function (PMID: 8071745, 8782044, 23045655). 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. - |
Alpha-N-acetylgalactosaminidase deficiency type 3 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 14, 2023 | Variant summary: NAGA c.479C>G (p.Ser160Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 251336 control chromosomes (gnomAD). c.479C>G has been reported in the literature as a compound heterozygous genotype in two siblings only one of whom was affected while the other remained unaffected at-least 5 years after initial follow up (example, Keulmans_1996, Bakker_2001). Although the alpha-NAGA activity in fibroblasts from the affected sibling was 4% of wild-type levels, the activity of the unaffected sibling was not reported. Therefore this does not support a variant specific impact on function. These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Clark_2012). The following publications have been ascertained in the context of this evaluation (PMID: 11313741, 34670123, 31980526, 23045655, 8782044, 11251574, 8071745). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=2) or VUS (n=5). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Alpha-N-acetylgalactosaminidase deficiency type 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Alpha-N-acetylgalactosaminidase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 24, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with alpha-N-acetylgalactosaminidase deficiency (MONDO#0017779). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. The clinical heterogeneity among individuals with alpha-N-acetylgalactosaminidase ranges from 'non-disease' to infantile neuroaxonal dystrophy (PMID:11313741). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (215 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Melibiase_2 (galactosidase A) domain (NCBI, DECIPHER, PDB). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0803 - This variant has limited previous evidence of pathogenicity. This variant has been reported as likely pathogenic or pathogenic (at least 5 times) and as a VUS (at least 5 times) across ClinVar and LOVD. In the literature, it has been reported in 2 siblings who were compound heterozygous for this variant and p.(Glu325Lys). However, only one sibling was reported as being clinically affected. The other sibling with the same genotype did not present with overt clinical symptoms at time of examination (PMID: 8782044; 11313741) (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Reduced α-NAGA activity in fibroblasts of one sibling compound heterozygous for p.(Ser160Cys) and p.(Glu325Lys). α-NAGA activity of the unaffected sibling was not tested (PMID: 8782044). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at