16-5025541-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016256.4(NAGPA):c.1485C>G(p.Asn495Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N495N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 35)
• Consequence: NAGPA NM_016256.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.656

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGPA	NM_016256.4	c.1485C>G	p.Asn495Lys	missense_variant	10/10	ENST00000312251.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGPA	ENST00000312251.8	c.1485C>G	p.Asn495Lys	missense_variant	10/10	1	NM_016256.4	P1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 80

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.57
MutPred		0.24		Gain of ubiquitination at N495 (P = 0.0014);.;
MVP		0.30
MPC		0.13
ClinPred		0.98	D
GERP RS		-7.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.73

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

LitVar

Other links and lift over

dbSNP: rs887854; hg19: chr16-5075542;