rs121434532

Positions:

• chr22-42067136-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

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).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: NAGA NM_000262.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:7
• Conservation: PhyloP100: 5.84

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-42067136-G-C is Pathogenic according to our data. Variant chr22-42067136-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 18165.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=7, Pathogenic=1, Likely_pathogenic=2}. Variant chr22-42067136-G-C is described in Lovd as [Pathogenic]. Variant chr22-42067136-G-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.24728158). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGA	NM_000262.3	c.479C>G	p.Ser160Cys	missense_variant	4/9	ENST00000396398.8	NP_000253.1
NAGA	NM_001362848.1	c.479C>G	p.Ser160Cys	missense_variant	5/10		NP_001349777.1
NAGA	NM_001362850.1	c.479C>G	p.Ser160Cys	missense_variant	5/10		NP_001349779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGA	ENST00000396398.8	c.479C>G	p.Ser160Cys	missense_variant	4/9	1	NM_000262.3	ENSP00000379680.3
NAGA	ENST00000402937.1	c.479C>G	p.Ser160Cys	missense_variant	5/10	5		ENSP00000384603.1
NAGA	ENST00000403363.5	c.479C>G	p.Ser160Cys	missense_variant	5/10	5		ENSP00000385283.1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000744 AC: 187 AN: 251336 Hom.: 0 AF XY: 0.000685 AC XY: 93 AN XY: 135852

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00199

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000696 AC: 1018 AN: 1461856 Hom.: 1 Cov.: 33 AF XY: 0.000664 AC XY: 483 AN XY: 727234

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.000782

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74444

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000576 Hom.: 0

Bravo AF: 0.000363

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000955 AC: 116

EpiCase AF: 0.000709

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19683538, 27138754, 23045655, 11313741, 31589614, 2372288, 8071745, 31980526, 11251574, 8782044, 34670123) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 27, 2021	- -

Alpha-N-acetylgalactosaminidase deficiency type 1 Pathogenic:1 Uncertain:2

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. -
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	Labcorp Genetics (formerly Invitae), Labcorp	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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;D;D
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	.;.;T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.71
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.064	T;T;T
Polyphen		0.10	B;B;B
Vest4		0.82
MVP		0.96
MPC		0.31
ClinPred		0.12	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.85
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs121434532; hg19: chr22-42463140; COSMIC: COSV67169893;