16-5033832-G-C

Variant names:

• chr16-5033832-G-C
• rs74952829
• NM_016256.4:c.83C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016256.4(NAGPA):​c.83C>G​(p.Ser28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. S28L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NAGPA NM_016256.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.458
• Publications: 2 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]

ALG1 (HGNC:18294): (ALG1 chitobiosyldiphosphodolichol beta-mannosyltransferase) The enzyme encoded by this gene catalyzes the first mannosylation step in the biosynthesis of lipid-linked oligosaccharides. This gene is mutated in congenital disorder of glycosylation type Ik. [provided by RefSeq, Dec 2008]

NAGPA-AS1 (HGNC:44184): (NAGPA antisense RNA 1)

ENSG00000267072 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07436916).

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.83C>G	p.Ser28Trp	missense	Exon 1 of 10	NP_057340.2	Q9UK23-1
	NAGPA-AS1	NR_038913.1		n.131G>C		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	ENST00000312251.8	TSL:1 MANE Select	c.83C>G	p.Ser28Trp	missense	Exon 1 of 10	ENSP00000310998.3	Q9UK23-1
	NAGPA	ENST00000948540.1		c.83C>G	p.Ser28Trp	missense	Exon 1 of 11	ENSP00000618599.1
	NAGPA	ENST00000948538.1		c.83C>G	p.Ser28Trp	missense	Exon 1 of 10	ENSP00000618597.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399572 Hom.: 0 Cov.: 34 AF XY: 0.00000145 AC XY: 1 AN XY: 690572

African (AFR) AF: 0.00 AC: 0 AN: 31748

American (AMR) AF: 0.00 AC: 0 AN: 35820

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25196

East Asian (EAS) AF: 0.00 AC: 0 AN: 35922

South Asian (SAS) AF: 0.00 AC: 0 AN: 79562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4686

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1080306

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 13

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		-0.46
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.035
Sift	Benign	0.19	T
Sift4G	Benign	0.19	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.18		Loss of disorder (P = 0.0106)
MVP		0.23
MPC		0.77
ClinPred		0.13	T
GERP RS		-0.26
PromoterAI		-0.078	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.051
gMVP		0.46

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: rs74952829; hg19: chr16-5083833;