16-5028124-G-C

Variant names:

• chr16-5028124-G-C
• rs139526942
• NM_016256.4:c.982C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016256.4(NAGPA):​c.982C>G​(p.Arg328Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000936 in 1,602,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R328C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: NAGPA NM_016256.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.984
• Publications: 9 publications found

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]

ENSG00000267072 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13691986).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016256.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	NM_016256.4	MANE Select	c.982C>G	p.Arg328Gly	missense	Exon 6 of 10	NP_057340.2	Q9UK23-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	ENST00000312251.8	TSL:1 MANE Select	c.982C>G	p.Arg328Gly	missense	Exon 6 of 10	ENSP00000310998.3	Q9UK23-1
	NAGPA	ENST00000948540.1		c.1084C>G	p.Arg362Gly	missense	Exon 7 of 11	ENSP00000618599.1
	NAGPA	ENST00000948538.1		c.982C>G	p.Arg328Gly	missense	Exon 6 of 10	ENSP00000618597.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000965 AC: 14 AN: 1450744 Hom.: 0 Cov.: 36 AF XY: 0.00000971 AC XY: 7 AN XY: 720924

African (AFR) AF: 0.00 AC: 0 AN: 33228

American (AMR) AF: 0.00 AC: 0 AN: 42872

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.000359 AC: 14 AN: 39010

South Asian (SAS) AF: 0.00 AC: 0 AN: 84852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106942

Other (OTH) AF: 0.00 AC: 0 AN: 59870

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 5

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.98
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.082
Sift	Benign	0.32	T
Sift4G	Benign	0.34	T
Polyphen		0.11	B
Vest4		0.24
MutPred		0.42		Loss of solvent accessibility (P = 0.0159)
MVP		0.41
MPC		0.018
ClinPred		0.50	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.55
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs139526942; hg19: chr16-5078125; COSMIC: COSV56569950; COSMIC: COSV56569950;