Genetic Variant NM_016256.4:c.1175-22_1175-16delTCCTCCC (chr16-5027394-TGGGAGGA-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_016256.4(NAGPA):c.1175-22_1175-16delTCCTCCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,608,326 control chromosomes in the GnomAD database, including 138,732 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.39 ( 11732 hom., cov: 0)

Exomes 𝑓: 0.41 ( 127000 hom. )

Consequence

NAGPA
NM_016256.4 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.20

Publications

2 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 16-5027394-TGGGAGGA-T is Benign according to our data. Variant chr16-5027394-TGGGAGGA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 260703.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.42 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAGPA	NM_016256.4 link	c.1175-22_1175-16delTCCTCCC		intron_variant	Intron 7 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.1175-22_1175-16delTCCTCCC		intron_variant	Intron 7 of 9	1	NM_016256.4	ENSP00000310998.3		Q9UK23-1

Frequencies

GnomAD3 genomes

AF:

0.393

AC:

59455

AN:

151294

Hom.:

11716

Cov.:

show subpopulations

Gnomad AFR

AF:

0.376

Gnomad AMI

AF:

0.381

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.448

Gnomad EAS

AF:

0.345

Gnomad SAS

AF:

0.395

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.424

Gnomad OTH

AF:

0.428

GnomAD2 exomes

AF:

0.382

AC:

94151

AN:

246258

AF XY:

0.392

show subpopulations

Gnomad AFR exome

AF:

0.369

Gnomad AMR exome

AF:

0.261

Gnomad ASJ exome

AF:

0.459

Gnomad EAS exome

AF:

0.345

Gnomad FIN exome

AF:

0.348

Gnomad NFE exome

AF:

0.418

Gnomad OTH exome

AF:

0.413

GnomAD4 exome

AF:

0.414

AC:

603491

AN:

1456908

Hom.:

127000

AF XY:

0.416

AC XY:

301830

AN XY:

724976

show subpopulations

African (AFR)

AF:

0.371

AC:

12388

AN:

33384

American (AMR)

AF:

0.269

AC:

12020

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.459

AC:

11969

AN:

26094

East Asian (EAS)

AF:

0.357

AC:

14149

AN:

39654

South Asian (SAS)

AF:

0.416

AC:

35801

AN:

86124

European-Finnish (FIN)

AF:

0.353

AC:

18730

AN:

53094

Middle Eastern (MID)

AF:

0.528

AC:

2943

AN:

5574

European-Non Finnish (NFE)

AF:

0.424

AC:

470126

AN:

1108118

Other (OTH)

AF:

0.421

AC:

25365

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

18435

36869

55304

73738

92173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14282

28564

42846

57128

71410

<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:

0.393

AC:

59505

AN:

151418

Hom.:

11732

Cov.:

AF XY:

0.389

AC XY:

28763

AN XY:

73956

show subpopulations

African (AFR)

AF:

0.376

AC:

15534

AN:

41314

American (AMR)

AF:

0.328

AC:

5000

AN:

15230

Ashkenazi Jewish (ASJ)

AF:

0.448

AC:

1553

AN:

3464

East Asian (EAS)

AF:

0.345

AC:

1755

AN:

5080

South Asian (SAS)

AF:

0.397

AC:

1911

AN:

4810

European-Finnish (FIN)

AF:

0.344

AC:

3614

AN:

10514

Middle Eastern (MID)

AF:

0.571

AC:

168

AN:

294

European-Non Finnish (NFE)

AF:

0.424

AC:

28737

AN:

67708

Other (OTH)

AF:

0.423

AC:

889

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1775

3551

5326

7102

8877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.304

Hom.:

1185

Bravo

AF:

0.393

Asia WGS

AF:

0.323

AC:

1123

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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