rs121434529
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP5BP4BS1_Supporting
The NM_000262.3(NAGA):c.973G>A(p.Glu325Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00365 in 1,614,138 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000262.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NAGA | NM_000262.3 | c.973G>A | p.Glu325Lys | missense_variant | Exon 8 of 9 | ENST00000396398.8 | NP_000253.1 | |
| NAGA | NM_001362848.1 | c.973G>A | p.Glu325Lys | missense_variant | Exon 9 of 10 | NP_001349777.1 | ||
| NAGA | NM_001362850.1 | c.973G>A | p.Glu325Lys | missense_variant | Exon 9 of 10 | NP_001349779.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NAGA | ENST00000396398.8 | c.973G>A | p.Glu325Lys | missense_variant | Exon 8 of 9 | 1 | NM_000262.3 | ENSP00000379680.3 | ||
| NAGA | ENST00000402937.1 | c.973G>A | p.Glu325Lys | missense_variant | Exon 9 of 10 | 5 | ENSP00000384603.1 | |||
| NAGA | ENST00000403363.5 | c.973G>A | p.Glu325Lys | missense_variant | Exon 9 of 10 | 5 | ENSP00000385283.1 |
Frequencies
GnomAD3 genomes 0.00217 AC: 331AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00247 AC: 622AN: 251354Hom.: 0 AF XY: 0.00261 AC XY: 355AN XY: 135868
GnomAD4 exome AF: 0.00380 AC: 5559AN: 1461822Hom.: 12 Cov.: 32 AF XY: 0.00377 AC XY: 2739AN XY: 727214
GnomAD4 genome 0.00217 AC: 331AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.00216 AC XY: 161AN XY: 74480
ClinVar
Submissions by phenotype
not provided Pathogenic:6
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Functional studies indicate this variant results in loss of alpha-N-acetylgalactosaminidase activity (Wang et al., 1990); This variant is associated with the following publications: (PMID: 17171432, 19683538, 29373990, 30487145, 8040340, 14685826, 8782044, 2243144, 11313741, 27138754, 29431110, 31980526, 31589614, 32860008) -
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NAGA: PP1:Strong, PS3:Moderate, PM2:Supporting, PM3:Supporting -
Alpha-N-acetylgalactosaminidase deficiency type 1 Pathogenic:5Uncertain:1
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This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 325 of the NAGA protein (p.Glu325Lys). This variant is present in population databases (rs121434529, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (PMID: 1131374, 7707696, 8040340, 8071745). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18162). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt NAGA protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects NAGA function (PMID: 2243144, 8782044, 11313741). For these reasons, this variant has been classified as Pathogenic. -
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Alpha-N-acetylgalactosaminidase deficiency type 2 Pathogenic:3Uncertain:1
Variant summary: NAGA c.973G>A (p.Glu325Lys) results in a conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of 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 0.0025 in 251354 control chromosomes (gnomAD). c.973G>A has been reported in the literature in multiple individuals affected with alpha-N-Acetylgalactosamidase defiency, primarily with infantile-onset (AKA Schindler disease; examples- Wang_1990, Keulemans_1996, Bakker_2001, Chabas_2007). These data indicate that the variant is very likely to be associated with disease. The variant has also been detected as both homozygous (e.g. Keulemans_1996) and compound heterozygous (e.g. Bakker_2001) in asymptomatic siblings of children with Schindler disease, indicating that this variant may result in a spectrum of clinical presentations. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal enzyme activity (examples: Wang_1990, Bakker_2001). Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The NAGA c.973G>A variant is classified as Likely Pathogenic (PS3, PM3_S, PP3, PP5) This variant is a single nucleotide change from a guanine to an adenine at position 973 which is predicted to change the glutamic acid at position 325 in the protein to lysine. The variant has been reported in both the homozygous and compound heterozygous states in multiple individuals affected with alpha-NAGA deficiency, with variable expressivity and reduced penetrance (PMID: 2243144, 8782044, 1313741) (PM3_S). Functional studies demostrated that this variant results significantly reduced in the alpha-NAGA enzyme activity (PMID: 2243144, 8040340, 14685826) (PS3). The variant is in dbSNP (rs121434529) and has been reported in population databases (gnomAD (v3.1.2) 331/152198, 0 homozygote). The variant has been reported in ClinVar (ID: 18162) and HGMD (Accession: CM900169) as a disease causing variant (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3). -
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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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Alpha-N-acetylgalactosaminidase deficiency Pathogenic:2
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. 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 glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (696 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated alpha galactosidase A C-terminal beta sandwich domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in many individuals with alpha-N-acetylgalactosaminidase (NAGA) deficiency and with variable clinical presentation (ClinVar, PMIDs: 11313741, 17171432). PMID:11313741 reported this variant as homozygous in a 3-year old proband with congenital cataract, slight motor retardation and secondary demyelinisation, and his 7-year old healthy sibling; both siblings had undetectable/profound deficiency in NAGA activity. (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Profound NAGA enzyme deficiency has been reported in tissue samples from individuals who are homozygous or compound heterozygous with this variant (PMIDs: 11313741, 17171432). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Alpha-N-acetylgalactosaminidase deficiency type 2;C1836544:Alpha-N-acetylgalactosaminidase deficiency type 1 Pathogenic:2
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PS3, PP3, PM3 -
not specified Pathogenic:1Uncertain:1
The p.Glu325Lys variant in NAGA has been previously reported in 4 individuals with Schindler disease: 3 in the homozygous state from consanguineous families, and one in the compound heterozygous state with another presumably pathogenic NAGA variant and segregated with disease in 1 affected family member (Wang 1990, Keulemans 1996, Bakker 2001, Clark 2009). However two siblings of two affected individuals had the p.Glu325Lys variant (1 homozygote and 1 compound heterozygote) but were clinically unaffected, despite reduced enzyme activity (Wang 1990, Wang 1994, Keulemans 1996, Bakker 2001, Clark 2009). Thus, variable expressivity and reduced penetrance has been suggested to occur in Schindler disease. The p.Glu325Lys variant has also been identified in 0.4% (515/129126) European chromosomes by gnomAD (http://gnomad.broadinstitute.org/), which is significantly higher than the maximum expected allele frequency for a rare disease. Computational prediction tools and conservation analyses suggest this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Glu325Lys variant is uncertain due to conflicting evidence. ACMG/AMP criteria applied: PM3, PS3_Supporting, BS1, BP4. -
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Inborn genetic diseases Pathogenic:1
The c.973G>A (p.E325K) alteration is located in exon 8 (coding exon 8) of the NAGA gene. This alteration results from a G to A substitution at nucleotide position 973, causing the glutamic acid (E) at amino acid position 325 to be replaced by a lysine (K). This mutation was identified in the homozygous state in multiple individuals with alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency and has been shown to segregate with disease (van Diggelen, 1987; Bakker, 2001). In one family, a sibling was clinically unaffected with negligible enzymatic activity, suggesting variable expressivity (Bakker, 2001). The p.E325K alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
NAGA-related disorder Pathogenic:1
The NAGA c.973G>A variant is predicted to result in the amino acid substitution p.Glu325Lys. This variant has been reported in the homozygous or compound heterozygous state in patients with enzymatic and/or biochemical test results consistent with alpha-N-acetylgalactosaminidase deficiency (Wang et al. 1990. PubMed ID: 2243144; Keulemans et al. 1996. PubMed ID: 8782044; Bakker et al. 2001. PubMed ID: 11313741; Chabás et al. 2007. PubMed ID: 17171432). In all of those studies, the p.Glu325Lys variant was reported to reduce enzyme activity to <1% of wild-type. Of note, the c.973G>A variant has been reported at an allele frequency of up to 0.41% in a large population database, which is relatively high for a pathogenic variant. However, based on its effect on NAGA enzyme activity, we classify the c.973G>A (p.Glu325Lys) variant as pathogenic. -
See cases Pathogenic:1
ACMG classification criteria: PS3, PM3, PP1, PP2, PP3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at