Genetic Variant NM_016256.4:c.683-29G>A (chr16-5030522-C-T) – ACMG Classification: Benign (-20 pts)

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.683-29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,531,390 control chromosomes in the GnomAD database, including 79,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6123 hom., cov: 32)

Exomes 𝑓: 0.32 ( 73318 hom. )

Consequence

NAGPA
NM_016256.4 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.633

Publications

5 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 (BayesDel_noAF=-0.81).

BP6

Variant 16-5030522-C-T is Benign according to our data. Variant chr16-5030522-C-T is described in ClinVar as Benign. ClinVar VariationId is 260707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGPA	NM_016256.4 link	c.683-29G>A		intron_variant	Intron 3 of 9	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.683-29G>A		intron_variant	Intron 3 of 9	1	NM_016256.4	ENSP00000310998.3		Q9UK23-1

Frequencies

GnomAD3 genomes

AF:

0.257

AC:

38984

AN:

151924

Hom.:

6126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0900

Gnomad AMI

AF:

0.332

Gnomad AMR

AF:

0.271

Gnomad ASJ

AF:

0.310

Gnomad EAS

AF:

0.162

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.468

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.332

Gnomad OTH

AF:

0.256

GnomAD2 exomes

AF:

0.281

AC:

43734

AN:

155862

AF XY:

0.276

show subpopulations

Gnomad AFR exome

AF:

0.0885

Gnomad AMR exome

AF:

0.267

Gnomad ASJ exome

AF:

0.296

Gnomad EAS exome

AF:

0.154

Gnomad FIN exome

AF:

0.452

Gnomad NFE exome

AF:

0.334

Gnomad OTH exome

AF:

0.280

GnomAD4 exome

AF:

0.318

AC:

438172

AN:

1379346

Hom.:

73318

Cov.:

AF XY:

0.313

AC XY:

213649

AN XY:

681602

show subpopulations

African (AFR)

AF:

0.0755

AC:

2363

AN:

31278

American (AMR)

AF:

0.270

AC:

9628

AN:

35682

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

7655

AN:

25086

East Asian (EAS)

AF:

0.180

AC:

6400

AN:

35652

South Asian (SAS)

AF:

0.169

AC:

13357

AN:

78868

European-Finnish (FIN)

AF:

0.450

AC:

22023

AN:

48898

Middle Eastern (MID)

AF:

0.168

AC:

952

AN:

5680

European-Non Finnish (NFE)

AF:

0.339

AC:

359597

AN:

1060882

Other (OTH)

AF:

0.283

AC:

16197

AN:

57320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

15100

30201

45301

60402

75502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11406

22812

34218

45624

57030

<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:

0.256

AC:

38972

AN:

152044

Hom.:

6123

Cov.:

AF XY:

0.259

AC XY:

19269

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.0897

AC:

3725

AN:

41516

American (AMR)

AF:

0.271

AC:

4135

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.310

AC:

1074

AN:

3470

East Asian (EAS)

AF:

0.161

AC:

833

AN:

5160

South Asian (SAS)

AF:

0.171

AC:

823

AN:

4818

European-Finnish (FIN)

AF:

0.468

AC:

4937

AN:

10546

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.332

AC:

22558

AN:

67938

Other (OTH)

AF:

0.253

AC:

533

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1394

2788

4182

5576

6970

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

394

788

1182

1576

1970

<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:

0.266

Hom.:

1626

Bravo

AF:

0.237

Asia WGS

AF:

0.174

AC:

608

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

9.8

(source)

DANN

Benign

0.66

PhyloP100

-0.63

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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