16-5030522-C-T

Variant names:

• chr16-5030522-C-T
• rs2102065
• NM_016256.4:c.683-29G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016256.4(NAGPA):​c.683-29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 1,531,390 control chromosomes in the GnomAD database, including 79,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6123 hom., cov: 32)
  • Exomes 𝑓: 0.32 (73318 hom.)
• Consequence: NAGPA NM_016256.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.633
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 16-5030522-C-T is Benign according to our data. Variant chr16-5030522-C-T is described in ClinVar as Benign. ClinVar VariationId is 260707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.328 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.683-29G>A		intron	N/A	NP_057340.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAGPA	ENST00000312251.8	TSL:1 MANE Select	c.683-29G>A		intron	N/A	ENSP00000310998.3
	NAGPA	ENST00000948540.1		c.683-29G>A		intron	N/A	ENSP00000618599.1
	NAGPA	ENST00000948538.1		c.683-29G>A		intron	N/A	ENSP00000618597.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38984 AN: 151924 Hom.: 6126 Cov.: 32

Gnomad AFR AF: 0.0900

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.281 AC: 43734 AN: 155862 AF XY: 0.276

Gnomad AFR exome AF: 0.0885

Gnomad AMR exome AF: 0.267

Gnomad ASJ exome AF: 0.296

Gnomad EAS exome AF: 0.154

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.280

GnomAD4 exome AF: 0.318 AC: 438172 AN: 1379346 Hom.: 73318 Cov.: 26 AF XY: 0.313 AC XY: 213649 AN XY: 681602

African (AFR) AF: 0.0755 AC: 2363 AN: 31278

American (AMR) AF: 0.270 AC: 9628 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7655 AN: 25086

East Asian (EAS) AF: 0.180 AC: 6400 AN: 35652

South Asian (SAS) AF: 0.169 AC: 13357 AN: 78868

European-Finnish (FIN) AF: 0.450 AC: 22023 AN: 48898

Middle Eastern (MID) AF: 0.168 AC: 952 AN: 5680

European-Non Finnish (NFE) AF: 0.339 AC: 359597 AN: 1060882

Other (OTH) AF: 0.283 AC: 16197 AN: 57320

GnomAD4 genome AF: 0.256 AC: 38972 AN: 152044 Hom.: 6123 Cov.: 32 AF XY: 0.259 AC XY: 19269 AN XY: 74280

African (AFR) AF: 0.0897 AC: 3725 AN: 41516

American (AMR) AF: 0.271 AC: 4135 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1074 AN: 3470

East Asian (EAS) AF: 0.161 AC: 833 AN: 5160

South Asian (SAS) AF: 0.171 AC: 823 AN: 4818

European-Finnish (FIN) AF: 0.468 AC: 4937 AN: 10546

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22558 AN: 67938

Other (OTH) AF: 0.253 AC: 533 AN: 2108

Alfa AF: 0.266 Hom.: 1626

Bravo AF: 0.237

Asia WGS AF: 0.174 AC: 608 AN: 3478

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	-0.81
CADD	Benign	9.8
DANN	Benign	0.66
PhyloP100		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2102065; hg19: chr16-5080523; COSMIC: COSV56569936; COSMIC: COSV56569936;