16-5033482-T-C

Variant names:

• chr16-5033482-T-C
• rs2972272
• NM_016256.4:c.333A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016256.4(NAGPA):​c.333A>G​(p.Gly111Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 1,569,762 control chromosomes in the GnomAD database, including 365,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35068 hom., cov: 33)
  • Exomes 𝑓: 0.68 (329938 hom.)
• Consequence: NAGPA NM_016256.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.42
• Publications: 17 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:):

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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-5033482-T-C is Benign according to our data. Variant chr16-5033482-T-C is described in ClinVar as Benign. ClinVar VariationId is 260706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

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.333A>G	p.Gly111Gly	synonymous	Exon 2 of 10	NP_057340.2
	NAGPA-AS1	NR_038913.1		n.-220T>C		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	ENST00000312251.8	TSL:1 MANE Select	c.333A>G	p.Gly111Gly	synonymous	Exon 2 of 10	ENSP00000310998.3
	NAGPA	ENST00000948540.1		c.333A>G	p.Gly111Gly	synonymous	Exon 2 of 11	ENSP00000618599.1
	NAGPA	ENST00000948538.1		c.333A>G	p.Gly111Gly	synonymous	Exon 2 of 10	ENSP00000618597.1

Frequencies

GnomAD3 genomes AF: 0.676 AC: 102641 AN: 151838 Hom.: 35029 Cov.: 33

Gnomad AFR AF: 0.660

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.713

Gnomad ASJ AF: 0.692

Gnomad EAS AF: 0.837

Gnomad SAS AF: 0.825

Gnomad FIN AF: 0.536

Gnomad MID AF: 0.838

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.698

GnomAD2 exomes AF: 0.705 AC: 126817 AN: 179764 AF XY: 0.711

Gnomad AFR exome AF: 0.646

Gnomad AMR exome AF: 0.733

Gnomad ASJ exome AF: 0.701

Gnomad EAS exome AF: 0.836

Gnomad FIN exome AF: 0.542

Gnomad NFE exome AF: 0.656

Gnomad OTH exome AF: 0.696

GnomAD4 exome AF: 0.680 AC: 963771 AN: 1417812 Hom.: 329938 Cov.: 89 AF XY: 0.685 AC XY: 481441 AN XY: 703192

African (AFR) AF: 0.662 AC: 21620 AN: 32652

American (AMR) AF: 0.727 AC: 29762 AN: 40914

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 17706 AN: 25450

East Asian (EAS) AF: 0.820 AC: 31126 AN: 37962

South Asian (SAS) AF: 0.825 AC: 68724 AN: 83270

European-Finnish (FIN) AF: 0.550 AC: 19615 AN: 35648

Middle Eastern (MID) AF: 0.811 AC: 3916 AN: 4828

European-Non Finnish (NFE) AF: 0.665 AC: 730133 AN: 1098148

Other (OTH) AF: 0.698 AC: 41169 AN: 58940

GnomAD4 genome AF: 0.676 AC: 102729 AN: 151950 Hom.: 35068 Cov.: 33 AF XY: 0.676 AC XY: 50190 AN XY: 74290

African (AFR) AF: 0.660 AC: 27358 AN: 41462

American (AMR) AF: 0.713 AC: 10904 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.692 AC: 2403 AN: 3472

East Asian (EAS) AF: 0.837 AC: 4287 AN: 5120

South Asian (SAS) AF: 0.825 AC: 3977 AN: 4818

European-Finnish (FIN) AF: 0.536 AC: 5661 AN: 10562

Middle Eastern (MID) AF: 0.825 AC: 241 AN: 292

European-Non Finnish (NFE) AF: 0.674 AC: 45803 AN: 67916

Other (OTH) AF: 0.701 AC: 1482 AN: 2114

Alfa AF: 0.670 Hom.: 6120

Bravo AF: 0.686

Asia WGS AF: 0.811 AC: 2805 AN: 3466

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.4
DANN	Benign	0.53
PhyloP100		-1.4
PromoterAI		0.074	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs2972272; hg19: chr16-5083483; COSMIC: COSV108151291; COSMIC: COSV108151291;