Variant 16-5033563-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016256.4(NAGPA):c.252C>G(p.His84Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,505,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Consequence

NAGPA
NM_016256.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 1.03

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:

NAGPA (HGNC:):

NAGPA links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10538703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAGPA	NM_016256.4 linkuse as main transcript	c.252C>G	p.His84Gln	missense_variant	2/10	ENST00000312251.8	NP_057340.2	Q9UK23-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAGPA	ENST00000312251.8 linkuse as main transcript	c.252C>G	p.His84Gln	missense_variant	2/10	1	NM_016256.4	ENSP00000310998.3		Q9UK23-1

Frequencies

GnomAD3 genomes

AF:

0.000454

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000180

AC:

AN:

110844

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

62582

show subpopulations

Gnomad AFR exome

AF:

0.000551

Gnomad AMR exome

AF:

0.0000546

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000106

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000318

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000399

AC:

540

AN:

1353642

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

270

AN XY:

667270

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

Gnomad4 AMR exome

AF:

0.0000677

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000264

Gnomad4 FIN exome

AF:

0.0000298

Gnomad4 NFE exome

AF:

0.000457

Gnomad4 OTH exome

AF:

0.000196

GnomAD4 genome

AF:

0.000453

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00108

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000553

Hom.:

Bravo

AF:

0.000544

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.0000434

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Stuttering, familial persistent, 2

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Nov 18, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.61

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.4

N;N

REVEL

Benign

0.20

Sift

Benign

0.11

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.25

B;.

Vest4

0.35

MutPred

0.63

Loss of methylation at R86 (P = 0.0464);Loss of methylation at R86 (P = 0.0464);

MVP

0.27

MPC

0.62

ClinPred

0.045

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over