dbSNP rs121434532: NAGA:p.Ser160Cys (chr22-42067136-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PS3PP5BP4BS1_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). ClinVar reports functional evidence for this variant: "SCV000221201: 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).". 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:7

Conservation

PhyloP100: 5.84

Publications

11 publications found

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 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: Genomics England PanelApp, G2P, Orphanet
alpha-N-acetylgalactosaminidase deficiency type 1
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
alpha-N-acetylgalactosaminidase deficiency type 3
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NAGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000221201: 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).

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

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	P17050
NAGA	NM_001362848.1		c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	NP_001349777.1	P17050
NAGA	NM_001362850.1		c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	NP_001349779.1	P17050

Ensembl Transcripts

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	P17050
NAGA	ENST00000898675.1		c.479C>G	p.Ser160Cys	missense	Exon 4 of 10	ENSP00000568734.1
NAGA	ENST00000402937.1	TSL:5	c.479C>G	p.Ser160Cys	missense	Exon 5 of 10	ENSP00000384603.1	P17050

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.000664

AC XY:

483

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00191

AC:

102

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000782

AC:

870

AN:

1112006

Other (OTH)

AF:

0.000613

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000479

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000691

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000576

Hom.:

Bravo

AF:

0.000363

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000955

AC:

116

EpiCase

AF:

0.000709

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Alpha-N-acetylgalactosaminidase deficiency type 1 (3)

Alpha-N-acetylgalactosaminidase deficiency (1)

Alpha-N-acetylgalactosaminidase deficiency type 2 (1)

Alpha-N-acetylgalactosaminidase deficiency type 3 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.10

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

M_CAP

Benign

0.069

MetaRNN

Benign

0.25

MetaSVM

Pathogenic

1.2

MutationAssessor

Uncertain

2.5

PhyloP100

5.8

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.71

Sift

Benign

0.17

Sift4G

Benign

0.064

Polyphen

0.10

Vest4

0.82

MVP

0.96

MPC

0.31

ClinPred

0.12

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over