rs121434529

Positions:

chr22-42061052-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM1PP5BP4BS1_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

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 12 hom. )

Consequence

NAGA
NM_000262.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:22U:3

Conservation

PhyloP100: 3.96

Variant links:

Genes affected

NAGA (HGNC:7631): (alpha-N-acetylgalactosaminidase) NAGA encodes the lysosomal enzyme alpha-N-acetylgalactosaminidase, which cleaves alpha-N-acetylgalactosaminyl moieties from glycoconjugates. Mutations in NAGA have been identified as the cause of Schindler disease types I and II (type II also known as Kanzaki disease). [provided by RefSeq, Jul 2008]

NAGA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a strand (size 7) in uniprot entity NAGAB_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000262.3

PP5

Variant 22-42061052-C-T is Pathogenic according to our data. Variant chr22-42061052-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18162.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=9, Pathogenic=11, Uncertain_significance=3}. Variant chr22-42061052-C-T is described in Lovd as [Pathogenic]. Variant chr22-42061052-C-T is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.18690613). . Strength limited to SUPPORTING due to the PP5.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0038 (5559/1461822) while in subpopulation NFE AF= 0.00451 (5012/1111986). AF 95% confidence interval is 0.0044. There are 12 homozygotes in gnomad4_exome. There are 2739 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NAGA	NM_000262.3 linkuse as main transcript	c.973G>A	p.Glu325Lys	missense_variant	8/9	ENST00000396398.8
NAGA	NM_001362848.1 linkuse as main transcript	c.973G>A	p.Glu325Lys	missense_variant	9/10
NAGA	NM_001362850.1 linkuse as main transcript	c.973G>A	p.Glu325Lys	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NAGA	ENST00000396398.8 linkuse as main transcript	c.973G>A	p.Glu325Lys	missense_variant	8/9	1	NM_000262.3	P1
NAGA	ENST00000402937.1 linkuse as main transcript	c.973G>A	p.Glu325Lys	missense_variant	9/10	5		P1
NAGA	ENST00000403363.5 linkuse as main transcript	c.973G>A	p.Glu325Lys	missense_variant	9/10	5		P1

Frequencies

GnomAD3 genomes

AF:

0.00217

AC:

331

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000850

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00381

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00247

AC:

622

AN:

251354

Hom.:

AF XY:

0.00261

AC XY:

355

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.00139

Gnomad NFE exome

AF:

0.00401

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00380

AC:

5559

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00377

AC XY:

2739

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.000961

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00245

Gnomad4 FIN exome

AF:

0.00140

Gnomad4 NFE exome

AF:

0.00451

Gnomad4 OTH exome

AF:

0.00316

GnomAD4 genome

AF:

0.00217

AC:

331

AN:

152316

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00381

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00357

Hom.:

Bravo

AF:

0.00223

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00360

AC:

ExAC

AF:

0.00250

AC:

304

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00354

EpiControl

AF:

0.00385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:22Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	NAGA: PP1:Strong, PS3:Moderate, PM2:Supporting, PM3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2021	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2022	- -

Alpha-N-acetylgalactosaminidase deficiency type 1

Pathogenic:5Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2001	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 23, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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). 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 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. -

Alpha-N-acetylgalactosaminidase deficiency type 2

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 27, 2021	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). -
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). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2020	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. -

Alpha-N-acetylgalactosaminidase deficiency

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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

Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 12, 2021	PS3, PP3, PM3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not specified

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 30, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Mar 30, 2023	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2020

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. -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Jul 07, 2019

ACMG classification criteria: PS3, PM3, PP1, PP2, PP3 -

NAGA-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 03, 2024

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.48

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;D;D

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

.;.;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.19

T;T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.7

H;H;H

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.3

D;D;D

REVEL

Pathogenic

0.80

Sift

Uncertain

0.023

D;D;D

Sift4G

Uncertain

0.026

D;D;D

Polyphen

0.31

B;B;B

Vest4

0.93

MVP

0.98

MPC

0.54

ClinPred

0.13

GERP RS

5.7

Varity_R

0.90

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over