22-42067136-G-C

Variant names:

• chr22-42067136-G-C
• rs121434532
• NM_000262.3:c.479C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP5 BP4 BS1_Supporting

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:
  • 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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• alpha-N-acetylgalactosaminidase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• alpha-N-acetylgalactosaminidase deficiency type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• alpha-N-acetylgalactosaminidase deficiency type 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• alpha-N-acetylgalactosaminidase deficiency type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• 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 VariationId is 18165.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24728158). . Strength limited to SUPPORTING due to the PP5.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000479 (73/152268) while in subpopulation NFE AF = 0.000691 (47/68008). AF 95% confidence interval is 0.000534. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000262.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGA	NM_000262.3	MANE Select	c.479C>G	p.Ser160Cys	missense	Exon 4 of 9	NP_000253.1
	NAGA	NM_001362848.1		c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	NP_001349777.1
	NAGA	NM_001362850.1		c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	NP_001349779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGA	ENST00000396398.8	TSL:1 MANE Select	c.479C>G	p.Ser160Cys	missense	Exon 4 of 9	ENSP00000379680.3
	NAGA	ENST00000402937.1	TSL:5	c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	ENSP00000384603.1
	NAGA	ENST00000403363.5	TSL:5	c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	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

GnomAD2 exomes AF: 0.000744 AC: 187 AN: 251336 AF XY: 0.000685

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00191 AC: 102 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.000782 AC: 870 AN: 1112006

Other (OTH) AF: 0.000613 AC: 37 AN: 60394

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

African (AFR) AF: 0.000168 AC: 7 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000691 AC: 47 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2116

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

Sep 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 27, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Dec 19, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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: 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.

Nov 26, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Alpha-N-acetylgalactosaminidase deficiency type 3 Pathogenic:1

Jun 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not specified Uncertain:1

Nov 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NAGA c.479C>G (p.Ser160Cys) results in a non-conservative amino acid change located in the Aldolase class I domain (IPR013785) 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 0.00068 in 1614124 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in NAGA causing Alpha-N Deficiency, allowing no conclusion about variant significance. c.479C>G has been reported in the literature in the compound heterozygous state in at least 1 individual affected with Alpha-N Deficiency (example, Keulemans_1996), however their sibling had the same genotype and was not clinically affected. These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity and undetectable protein expression in patient fibroblasts (example, Keulemans_1996), further a maturation defect has also been noted in vitro (Clark_2012). ClinVar contains an entry for this variant (Variation ID: 18165). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Alpha-N-acetylgalactosaminidase deficiency type 2 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 24, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
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
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.71
Sift	Benign	0.17	T
Sift4G	Benign	0.064	T
Polyphen		0.10	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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

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