dbSNP rs887854: NAGPA:p.Asn495Asn (chr16-5025541-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_016256.4(NAGPA):c.1485C>T(p.Asn495Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,613,186 control chromosomes in the GnomAD database, including 365,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.72 ( 40019 hom., cov: 35)

Exomes 𝑓: 0.66 ( 325145 hom. )

Consequence

NAGPA
NM_016256.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.656

Publications

25 publications found

Variant links:

Genes affected

NAGPA (HGNC:17378): (N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase) Hydrolases are transported to lysosomes after binding to mannose 6-phosphate receptors in the trans-Golgi network. This gene encodes the enzyme that catalyzes the second step in the formation of the mannose 6-phosphate recognition marker on lysosomal hydrolases. Commonly known as 'uncovering enzyme' or UCE, this enzyme removes N-acetyl-D-glucosamine (GlcNAc) residues from GlcNAc-alpha-P-mannose moieties and thereby produces the recognition marker. The encoded preproprotein is proteolytically processed by furin to generate the mature enzyme, a homotetramer of two disulfide-linked homodimers. Mutations in this gene are associated with developmental stuttering in human patients. [provided by RefSeq, Oct 2015]

NAGPA links:

ENSG00000267072 (HGNC:):

ENSG00000267072 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 16-5025541-G-A is Benign according to our data. Variant chr16-5025541-G-A is described in ClinVar as Benign. ClinVar VariationId is 260705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.656 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGPA	NM_016256.4 link	c.1485C>T	p.Asn495Asn	synonymous_variant	Exon 10 of 10	ENST00000312251.8	NP_057340.2	Q9UK23-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAGPA	ENST00000312251.8 link	c.1485C>T	p.Asn495Asn	synonymous_variant	Exon 10 of 10	1	NM_016256.4	ENSP00000310998.3		Q9UK23-1

Frequencies

GnomAD3 genomes

AF:

0.717

AC:

109047

AN:

152110

Hom.:

39962

Cov.:

show subpopulations

Gnomad AFR

AF:

0.860

Gnomad AMI

AF:

0.662

Gnomad AMR

AF:

0.710

Gnomad ASJ

AF:

0.654

Gnomad EAS

AF:

0.835

Gnomad SAS

AF:

0.817

Gnomad FIN

AF:

0.532

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.717

GnomAD2 exomes

AF:

0.697

AC:

175049

AN:

251280

AF XY:

0.698

show subpopulations

Gnomad AFR exome

AF:

0.862

Gnomad AMR exome

AF:

0.721

Gnomad ASJ exome

AF:

0.663

Gnomad EAS exome

AF:

0.840

Gnomad FIN exome

AF:

0.546

Gnomad NFE exome

AF:

0.643

Gnomad OTH exome

AF:

0.679

GnomAD4 exome

AF:

0.663

AC:

969259

AN:

1460958

Hom.:

325145

Cov.:

AF XY:

0.668

AC XY:

485382

AN XY:

726774

show subpopulations

African (AFR)

AF:

0.872

AC:

29171

AN:

33458

American (AMR)

AF:

0.716

AC:

32040

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.655

AC:

17107

AN:

26136

East Asian (EAS)

AF:

0.819

AC:

32503

AN:

39700

South Asian (SAS)

AF:

0.817

AC:

70472

AN:

86210

European-Finnish (FIN)

AF:

0.546

AC:

29045

AN:

53242

Middle Eastern (MID)

AF:

0.793

AC:

4101

AN:

5174

European-Non Finnish (NFE)

AF:

0.641

AC:

713225

AN:

1111988

Other (OTH)

AF:

0.689

AC:

41595

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

20390

40780

61169

81559

101949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19012

38024

57036

76048

95060

<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:

0.717

AC:

109166

AN:

152228

Hom.:

40019

Cov.:

AF XY:

0.716

AC XY:

53288

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.860

AC:

35762

AN:

41562

American (AMR)

AF:

0.710

AC:

10863

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.654

AC:

2272

AN:

3472

East Asian (EAS)

AF:

0.835

AC:

4314

AN:

5168

South Asian (SAS)

AF:

0.818

AC:

3952

AN:

4834

European-Finnish (FIN)

AF:

0.532

AC:

5635

AN:

10588

Middle Eastern (MID)

AF:

0.833

AC:

245

AN:

294

European-Non Finnish (NFE)

AF:

0.647

AC:

44001

AN:

67996

Other (OTH)

AF:

0.721

AC:

1521

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1579

3158

4736

6315

7894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

836

1672

2508

3344

4180

<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:

0.676

Hom.:

104395

Bravo

AF:

0.735

Asia WGS

AF:

0.812

AC:

2822

AN:

3478

EpiCase

AF:

0.656

EpiControl

AF:

0.654

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.88

(source)

DANN

Benign

0.78

PhyloP100

-0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over