dbSNP rs121434532: NAGA:p.Ser160Phe (chr22-42067136-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_000262.3(NAGA):c.479C>T(p.Ser160Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S160C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NAGA
NM_000262.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.84

Publications

0 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: 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

NAGA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-42067136-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 18165.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NAGA	NM_000262.3 link	c.479C>T	p.Ser160Phe	missense_variant	Exon 4 of 9	ENST00000396398.8	NP_000253.1
NAGA	NM_001362848.1 link	c.479C>T	p.Ser160Phe	missense_variant	Exon 5 of 10		NP_001349777.1
NAGA	NM_001362850.1 link	c.479C>T	p.Ser160Phe	missense_variant	Exon 5 of 10		NP_001349779.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NAGA	ENST00000396398.8 link	c.479C>T	p.Ser160Phe	missense_variant	Exon 4 of 9	1	NM_000262.3	ENSP00000379680.3
NAGA	ENST00000402937.1 link	c.479C>T	p.Ser160Phe	missense_variant	Exon 5 of 10	5		ENSP00000384603.1
NAGA	ENST00000403363.5 link	c.479C>T	p.Ser160Phe	missense_variant	Exon 5 of 10	5		ENSP00000385283.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112006

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.90

D;D;D

Eigen

Benign

0.060

Eigen_PC

Benign

0.051

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.0

.;.;D

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.2

MutationAssessor

Uncertain

2.7

M;M;M

PhyloP100

5.8

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Pathogenic

0.76

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.18

T;T;T

Vest4

0.83

ClinPred

0.95

GERP RS

4.5

Varity_R

0.81

gMVP

0.98

Mutation Taster

=39/61

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over