16-5025632-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_016256.4(NAGPA):c.1394C>T(p.Thr465Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,613,428 control chromosomes in the GnomAD database, including 92,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.28 (6802 hom., cov: 32)
  • Exomes 𝑓: 0.33 (85371 hom.)
• Consequence: NAGPA NM_016256.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7043948E-4).
• BP6: Variant 16-5025632-G-A is Benign according to our data. Variant chr16-5025632-G-A is described in ClinVar as [Benign]. Clinvar id is 260704.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NAGPA	NM_016256.4	c.1394C>T	p.Thr465Ile	missense_variant	10/10	ENST00000312251.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NAGPA	ENST00000312251.8	c.1394C>T	p.Thr465Ile	missense_variant	10/10	1	NM_016256.4	P1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42134 AN: 151994 Hom.: 6804 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.338

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.277

GnomAD3 exomes AF: 0.299 AC: 74432 AN: 248632 Hom.: 12474 AF XY: 0.298 AC XY: 40122 AN XY: 134574

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.160

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.356

Gnomad OTH exome AF: 0.319

GnomAD4 exome AF: 0.334 AC: 488004 AN: 1461316 Hom.: 85371 Cov.: 68 AF XY: 0.329 AC XY: 239450 AN XY: 726938

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.335

Gnomad4 EAS exome AF: 0.181

Gnomad4 SAS exome AF: 0.176

Gnomad4 FIN exome AF: 0.454

Gnomad4 NFE exome AF: 0.357

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.277 AC: 42125 AN: 152112 Hom.: 6802 Cov.: 32 AF XY: 0.278 AC XY: 20687 AN XY: 74362

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.338

Gnomad4 EAS AF: 0.164

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.351

Gnomad4 OTH AF: 0.273

Alfa AF: 0.333 Hom.: 17823

Bravo AF: 0.259

TwinsUK AF: 0.345 AC: 1280

ALSPAC AF: 0.366 AC: 1412

ESP6500AA AF: 0.133 AC: 586

ESP6500EA AF: 0.349 AC: 3005

ExAC AF: 0.294 AC: 35729

Asia WGS AF: 0.179 AC: 626 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.014
Dann	Benign	0.40
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.53	T;T
MetaRNN	Benign	0.00017	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.041
Sift	Benign	0.43	T;T
Sift4G	Benign	0.095	T;T
Polyphen		0.0	B;B
Vest4		0.083
MPC		0.017
ClinPred		0.013	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.44

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7188856; hg19: chr16-5075633; COSMIC: COSV56569290; COSMIC: COSV56569290;