16-5025541-G-A

Variant names:

• chr16-5025541-G-A
• rs887854
• NM_016256.4:c.1485C>T

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.1485C>T​(p.Asn495Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.669 in 1,613,186 control chromosomes in the GnomAD database, including 365,164 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40019 hom., cov: 35)
  • Exomes 𝑓: 0.66 (325145 hom.)
• Consequence: NAGPA NM_016256.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.656
• Publications: 25 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-5025541-G-A is Benign according to our data. Variant chr16-5025541-G-A is described in ClinVar as Benign. ClinVar VariationId is 260705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.656 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.853 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	NM_016256.4	MANE Select	c.1485C>T	p.Asn495Asn	synonymous	Exon 10 of 10	NP_057340.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	ENST00000312251.8	TSL:1 MANE Select	c.1485C>T	p.Asn495Asn	synonymous	Exon 10 of 10	ENSP00000310998.3
	NAGPA	ENST00000381955.7	TSL:5	c.1383C>T	p.Asn461Asn	synonymous	Exon 9 of 9	ENSP00000371381.3
	NAGPA	ENST00000563578.5	TSL:3	c.882C>T	p.Asn294Asn	synonymous	Exon 5 of 5	ENSP00000467385.1

Frequencies

GnomAD3 genomes AF: 0.717 AC: 109047 AN: 152110 Hom.: 39962 Cov.: 35

Gnomad AFR AF: 0.860

Gnomad AMI AF: 0.662

Gnomad AMR AF: 0.710

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.835

Gnomad SAS AF: 0.817

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.647

Gnomad OTH AF: 0.717

GnomAD2 exomes AF: 0.697 AC: 175049 AN: 251280 AF XY: 0.698

Gnomad AFR exome AF: 0.862

Gnomad AMR exome AF: 0.721

Gnomad ASJ exome AF: 0.663

Gnomad EAS exome AF: 0.840

Gnomad FIN exome AF: 0.546

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.679

GnomAD4 exome AF: 0.663 AC: 969259 AN: 1460958 Hom.: 325145 Cov.: 80 AF XY: 0.668 AC XY: 485382 AN XY: 726774

African (AFR) AF: 0.872 AC: 29171 AN: 33458

American (AMR) AF: 0.716 AC: 32040 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 17107 AN: 26136

East Asian (EAS) AF: 0.819 AC: 32503 AN: 39700

South Asian (SAS) AF: 0.817 AC: 70472 AN: 86210

European-Finnish (FIN) AF: 0.546 AC: 29045 AN: 53242

Middle Eastern (MID) AF: 0.793 AC: 4101 AN: 5174

European-Non Finnish (NFE) AF: 0.641 AC: 713225 AN: 1111988

Other (OTH) AF: 0.689 AC: 41595 AN: 60328

GnomAD4 genome AF: 0.717 AC: 109166 AN: 152228 Hom.: 40019 Cov.: 35 AF XY: 0.716 AC XY: 53288 AN XY: 74426

African (AFR) AF: 0.860 AC: 35762 AN: 41562

American (AMR) AF: 0.710 AC: 10863 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2272 AN: 3472

East Asian (EAS) AF: 0.835 AC: 4314 AN: 5168

South Asian (SAS) AF: 0.818 AC: 3952 AN: 4834

European-Finnish (FIN) AF: 0.532 AC: 5635 AN: 10588

Middle Eastern (MID) AF: 0.833 AC: 245 AN: 294

European-Non Finnish (NFE) AF: 0.647 AC: 44001 AN: 67996

Other (OTH) AF: 0.721 AC: 1521 AN: 2110

Alfa AF: 0.676 Hom.: 104395

Bravo AF: 0.735

Asia WGS AF: 0.812 AC: 2822 AN: 3478

EpiCase AF: 0.656

EpiControl AF: 0.654

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.88
DANN	Benign	0.78
PhyloP100		-0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs887854; hg19: chr16-5075542; COSMIC: COSV56570361; COSMIC: COSV56570361;