rs7188856

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016256.4(NAGPA):c.1394C>T(p.Thr465Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,428 control chromosomes in the GnomAD database, including 92,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 6802 hom., cov: 32)

Exomes 𝑓: 0.33 ( 85371 hom. )

Consequence

NAGPA
NM_016256.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.45

Publications

33 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7043948E-4).

BP6

Variant 16-5025632-G-A is Benign according to our data. Variant chr16-5025632-G-A is described in ClinVar as Benign. ClinVar VariationId is 260704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGPA	NM_016256.4 link	c.1394C>T	p.Thr465Ile	missense_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.1394C>T	p.Thr465Ile	missense_variant	Exon 10 of 10	1	NM_016256.4	ENSP00000310998.3		Q9UK23-1

Frequencies

GnomAD3 genomes

AF:

0.277

AC:

42134

AN:

151994

Hom.:

6804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.124

Gnomad AMI

AF:

0.339

Gnomad AMR

AF:

0.286

Gnomad ASJ

AF:

0.338

Gnomad EAS

AF:

0.164

Gnomad SAS

AF:

0.175

Gnomad FIN

AF:

0.467

Gnomad MID

AF:

0.150

Gnomad NFE

AF:

0.351

Gnomad OTH

AF:

0.277

GnomAD2 exomes

AF:

0.299

AC:

74432

AN:

248632

AF XY:

0.298

show subpopulations

Gnomad AFR exome

AF:

0.121

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.328

Gnomad EAS exome

AF:

0.160

Gnomad FIN exome

AF:

0.454

Gnomad NFE exome

AF:

0.356

Gnomad OTH exome

AF:

0.319

GnomAD4 exome

AF:

0.334

AC:

488004

AN:

1461316

Hom.:

85371

Cov.:

AF XY:

0.329

AC XY:

239450

AN XY:

726938

show subpopulations

African (AFR)

AF:

0.111

AC:

3723

AN:

33470

American (AMR)

AF:

0.280

AC:

12508

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

8760

AN:

26126

East Asian (EAS)

AF:

0.181

AC:

7174

AN:

39696

South Asian (SAS)

AF:

0.176

AC:

15136

AN:

86238

European-Finnish (FIN)

AF:

0.454

AC:

24199

AN:

53334

Middle Eastern (MID)

AF:

0.179

AC:

1001

AN:

5590

European-Non Finnish (NFE)

AF:

0.357

AC:

397058

AN:

1111824

Other (OTH)

AF:

0.306

AC:

18445

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

21600

43201

64801

86402

108002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12352

24704

37056

49408

61760

<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:

0.277

AC:

42125

AN:

152112

Hom.:

6802

Cov.:

AF XY:

0.278

AC XY:

20687

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.124

AC:

5155

AN:

41532

American (AMR)

AF:

0.286

AC:

4370

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

1172

AN:

3470

East Asian (EAS)

AF:

0.164

AC:

843

AN:

5154

South Asian (SAS)

AF:

0.174

AC:

841

AN:

4824

European-Finnish (FIN)

AF:

0.467

AC:

4941

AN:

10570

Middle Eastern (MID)

AF:

0.154

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.351

AC:

23875

AN:

67964

Other (OTH)

AF:

0.273

AC:

574

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1497

2993

4490

5986

7483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

420

840

1260

1680

2100

<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:

0.327

Hom.:

32619

Bravo

AF:

0.259

TwinsUK

AF:

0.345

AC:

1280

ALSPAC

AF:

0.366

AC:

1412

ESP6500AA

AF:

0.133

AC:

586

ESP6500EA

AF:

0.349

AC:

3005

ExAC

AF:

0.294

AC:

35729

Asia WGS

AF:

0.179

AC:

626

AN:

3478

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

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.014

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.20

T;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.53

T;T

MetaRNN

Benign

0.00017

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.1

L;.

PhyloP100

-1.4

PrimateAI

Benign

0.29

PROVEAN

Benign

0.010

N;N

REVEL

Benign

0.041

Sift

Benign

0.43

T;T

Sift4G

Benign

0.095

T;T

Polyphen

0.0

B;B

Vest4

0.083

MPC

0.017

ClinPred

0.013

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.44

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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